Nature Comms: Acute viral infection accelerates neurodegeneration in a mouse model of ALS

 

#19,319

One of the great - yet unanswered - questions about acute viral illnesses is what role (if any) do they play in the development of neurodegenerative diseases, perhaps years or even decades later? 

A hundred years ago the world was embroiled in a global epidemic of Encephalitis Lethargica (EL) following the 1918 influenza pandemic, which appears to have affected millions of people.  

While a viral cause is suspected, it isn't clear whether it was sequelae from the  H1N1 influenza virus, or from some other viral agent (see Evidence for an enterovirus as the cause of encephalitis lethargica).

Throughout history, there have been other reports of neurological outbreaks following severe epidemics, including febris comatosa which sparked a severe outbreak in London between 1673 and 1675, and following the 1889–1890 influenza (?) pandemic, a severe wave of somnolent illnesses (nicknamed the "Nona") was described in Italy

Among those who survived, Parkinsonism and other neurological sequelae was common. 

Over the past 6 years, we've seen numerous reports of memory and neurological problems associated with COVID infection, including 2025's BMC Neurology: Long-term Neurological and Cognitive Impact of COVID-19: A Systematic Review and Meta-analysis in over 4 Million Patients. 

While this is an extensive review - and its 16-page PDF deserves careful review - briefly, they report fatigue affecting over 40% of patients and memory disorders affecting nearly 30%, at least 6 months post infection.

More broadly, in 2023 we looked at a study (see Neuron: Virus Exposure and Neurodegenerative Disease Risk Across National Biobanks), which found statistical linkage between viral illnesses and developing neurodegenerative diseases in the future.

With the very strong caveat that the exact cause of Alzheimer's, Parkinson's, and other neurodegenerative diseases are not yet known - and all are likely the result of multiple genetic and environmental factors - the role of infectious diseases is a hypothesis under serious investigation.

All of which brings us to a report in Nature Communications which reports that  a single, nonfatal respiratory virus infection appears to hasten ALS-like disease in genetically susceptible mice (SOD1-G93A mutation). 

ALS-susceptible mice were infected before they showed motor symptoms with either influenza A (H1N1) or SARS-CoV-2 and compared with uninfected (SOD1-G93A) mice. 

• Influenza-infected mice developed declining motor performance earlier and reached severe ALS-related endpoints sooner. 

• SARS-CoV-2 infected mice saw similar declines in motor ability, but their endpoint was not significantly shortened.  

While this isn't proof that flu or COVID-19 causes ALS or accelerates neurodegenerative disease in humans, it is another datapoint to consider. Although peer-reviewed, the final version will be uploaded when completed. 

Due to its length and technical nature, I've only posted the Abstract. Follow the link to read it in its entirety.  I'll have a postscript after the break. 

Acute viral infection accelerates neurodegeneration in a mouse model of ALS

Art Marzok, Jonathan P. Mapletoft, Imran Ahmed, Braeden Cowbrough, Daniel B. Celeste, Michael R. D’Agostino, Jann C. Ang, Andrew T. Chen, Vithushan Surendran, Yona Tugg, Hahn Li, Karena Wong, Anna Dvorkin-Gheva, Ali Zhang,
Hannah D. Stacey, Mannie Lam, Yasmine Kollar, Kevin R. Milnes, Sam Afkhami & Matthew S. Miller

Nature Communications (2026) Cite this article
 
PDF

We’re sharing this article early to provide faster access to peer-reviewed, accepted research. It is citable and carries a permanent DOI. This version is subject to further edits and will be replaced automatically by the final Version of Record. All legal disclaimers apply.

Abstract

While several viral infections have been associated with amyotrophic lateral sclerosis (ALS), the mechanism(s) through which they promote disease remains elusive. Here we investigate the impact of common, acute viral infections on ALS disease onset and progression in the SOD1G93A mouse model. 

A single sublethal infection prior to onset of ALS clinical signs is associated with markedly accelerated ALS disease progression characterized by rapid loss of hindlimb function. Prior infection results in gliosis in the lumbar spine and upregulation of transcriptional pathways involved in inflammatory responses, metabolic dysregulation, and muscular dysfunction. Therapeutic suppression of gliosis with an anti-inflammatory small molecule, or administration of a direct-acting antiviral, is associated with significantly improved ALS clinical signs, akin to what is observed in uninfected animals. 

Our study provides causal and mechanistic evidence that the immune response elicited by acute viral infections may be an important etiological factor that alters ALS disease trajectory.

        (Continue . . .) 

Although the link between COVID/Flu infection and neurodegenerative diseases later in life is far from established, over the past 15 years we've seen numerous studies that have linked heart attacks and strokes to acute influenza and respiratory infections.

At the same time, we've seen growing evidence that the uptake of the seasonal flu vaccine may reduce the incidence of heart attack and stroke, even if the vaccine doesn't prevent influenza infection. 

Eurosurveillance: Influenza Vaccination Attenuates Acute Myocardial Infarction and Stroke Risk Following Influenza Infection

Conclusions

Our findings add to the evidence that influenza vaccination confers cardiovascular protection. In this study, prior vaccination halved the excess risk of acute myocardial infarction or stroke following breakthrough influenza infection.   

Which is why I'll be rolling up my sleeve again for my 21st consecutive yearly flu shot later this month, and why I'll be getting the updated COVID shot when it becomes available. 

If they turn out to be neuroprotective as well, I'll consider it a welcome bonus. 

Eurosurveillance: Influenza Vaccination Attenuates Acute Myocardial Infarction and Stroke Risk Following Influenza Infection

#19,105

Ask almost any paramedic, ER doctor, or ICU nurse and they will tell you that heart attacks and strokes are more common in the winter. So much so, that these events are commonly called `Christmas Coronaries’ or `Holiday Heart Attacks’.

In 1998, a study looked at the rate of heart attacks in the United States (see Seasonal distribution of acute myocardial infarction in the second National Registry of Myocardial Infarction), and found that Acute Myocardial Infarctions (AMIs) ran as much 53% higher during the winter months than during the summer.

While cold weather combined with strenuous physical activity (like clearing snow from sidewalks) has often been blamed for this spike, even in balmy Southern California, studies have shown a 33% increase in heart attacks over the holidays (see When Throughout the Year Is Coronary Death Most Likely to Occur?).

Admittedly, non-climate related factors – like overindulgence in food and drink - combined with holiday stressors like shopping, running up debt, traveling, meal preparation, and the angst that comes from dysfunctional family gatherings are all plausible contributors to this yearly spike.

But over the past 15 years studies have increasingly linked this seasonal increase in heart attacks and strokes to acute influenza and respiratory infections. A few (of many) studies include:

Risk of Cardiovascular Events After Influenza: A Population-based Self Controlled Case Series Study

PloS One: Early Risk of Acute Myocardial Infarction Following Hospitalization for Severe Influenza

JAHA: Another Study Linking ILI To Increased Risk Of Heart Attack & Stroke

PLoS One: Transient Depression of Myocardial Function After Influenza Virus Infection

NEJM: Acute Myocardial Infarction After Laboratory-Confirmed Influenza Infection

Eur. Resp.J.: Influenza & Pneumonia Infections Increase Risk Of Heart Attack and Stroke

At the same time, we've seen growing evidence that the uptake of the seasonal flu vaccine may reduce the incidence of heart attack and stroke, even if the vaccine doesn't prevent influenza infection.

Nature: Influenza Vaccination & Major Cardiovascular Risk: a Systematic Review & Meta-Analysis

The Lancet: Influenza Vaccine to Reduce Adverse Vascular Events in Patients with Heart Failure

AHA: Study Shows Flu Shots Reduce Deaths From Heart Failure

All of which brings us to a new study, published yesterday in Eurosurveillance, which seeks to confirm and expand upon these earlier findings using Danish national health records from across the 2014-2025 influenza seasons.

They found that people (age 40+) with a confirmed flu infection were more likely to be hospitalized for a heart attack or stroke in the first 7 days after testing positive. The risk was highest in the first 3 days, and returned to normal after 2 weeks. 

Intriguingly, they found the short-term risk was reduced by about 50% among those with a positive influenza test, but vaccinated.  

Today's study is quite detailed, and many will want to read it in its entirety. I've only reproduced the link, and summary, followed by a link to an accompanying editorial. 

I'll return with a brief postscript about an unexpected finding after the break.  

Influenza vaccination attenuates acute myocardial infarction and stroke risk following influenza infection: a register-based, self-controlled case series study, Denmark, 2014 to 2025  
Roberto Croci1,2,* , Johanna J Young2,* , Hanne-Dorthe Emborg2 , Palle Valentiner-Branth2 , Steen Ethelberg2,3 , Christian Holm Hansen2 

What did you want to address in this study and why?

Catching influenza increases the short-term risk of heart attack and stroke. Influenza vaccination has been shown to reduce this risk by preventing infection, but it is unclear whether it also offers protection among people who become infected despite vaccination. We wanted to quantify how much more at risk of heart attack and stroke adults in Denmark are shortly after catching influenza, and to assess if prior vaccination can attenuate this risk.

What have we learnt from this study?

In adults 40 years or older in Denmark, hospital admissions for heart attack and stroke were more frequent in the first week after testing positive for influenza than during any other period in the year before and after their test, almost threefold for stroke and fivefold for heart attack. This increased risk was about half as high among people who tested positive for influenza but had received the influenza vaccine that season.

What are the implications of your findings for public health?

Influenza vaccination may offer cardiovascular protection even in instances when it does not prevent infection. If confirmed by additional studies in other settings, this would strengthen the case for prioritising influenza vaccination among people at risk of heart disease or stroke and would support refining recommendations across Europe.

       (SNIP)

      Conclusions

Our findings add to the evidence that influenza vaccination confers cardiovascular protection. In this study, prior vaccination halved the excess risk of acute myocardial infarction or stroke following breakthrough influenza infection. These results strengthen the case for prioritising influenza vaccination in high-risk groups. Highlighting the dual protection offered by vaccination, against both infection and its cardiovascular complications, could have a substantial public health impact. Factoring this into economic and burden analysis might improve the cost-effectiveness profile of vaccination programmes.

       (Continue . . . )

        Editorial

Does influenza vaccination protect people with breakthrough infections from acute cardiovascular events?
Jeffrey C Kwong

Of note, the authors of this study used a (bacterial, non-respiratory) laboratory-confirmed Campylobacter spp. infection as a negative control group, and found a similar increase in cardiac risk to influenza infection.   

Unlike with influenza, previous flu vaccination showed no attenuating effect. 

They wrote:

Unexpectedly, infection with Campylobacter spp., a food-borne, non-respiratory bacterial pathogen, was associated with a threefold increase in acute cardiovascular events.

One explanation may be that any infection severe enough to warrant microbiological testing can result in proinflammatory events. Alternatively, unmeasured respiratory co-infections might have determined the risk increase, at least in part.

Meta-analyses have shown that respiratory pathogens other than influenza can trigger acute cardiovascular events [24]. Research should clarify whether this is true for non-respiratory pathogens as well. Importantly, the absence of effect modification by influenza vaccination in our Campylobacter-negative exposure analysis reinforces that the observed risk attenuation after influenza infection is exposure-specific. 

While cardiac complications have been reported following Campylobacter infection (see Review of Campylobacter Species Related Cardiac Disease), today's findings suggest this may be more common than previously believed.

Although the current flu vaccine is nowhere near as effective as we'd like it to be, and the promise of a universal flu vaccine remains elusive (see J.I.D.: NIAID's Strategic Plan To Develop A Universal Flu Vaccine), we continue to see evidence that the benefits of vaccination may extend beyond simply reducing the risk of influenza infection. 

Which is why I'll be rolling up my sleeve this fall for both the Flu and COVID vaccines. Because at my age - and in my physical condition - I can use all the advantages I can get. 

When Seasonal Flu Exceeds Expectations

Flu Virus binding to Receptor Cells – Credit CDC

#19,006

It is summer down under, and typically the nadir of the Australian flu season, but this year - as Virologist and blogger Dr. Ian McKay reports - seasonal flu is still going strong more than 3 months after their calendar-based flu season should have ended. 

A few days ago Ian wrote: 

Instead of the annual epidemic returning to baseline levels, cases stopped declining in October and have started to rise again in November, December, and perhaps also in January (still a few days left). Just to note, there is always some flu around, just usually at very low levels outside the epidemic peak period.

I would invite you to read Ian's entire analysis, because the same subclade K of seasonal H3N2 which emerged there last July, is now running roughshod over the United States, Canada, Europe, Asia, and the rest of the Northern Hemisphere. 

Due to the holidays, surveillance and reporting over the past few weeks have  likely under-represented its current impact here in the United States. We'll get another belated FluView on Monday, but it often takes until mid-January before reporting returns to normal. 

Meanwhile, early reports (see WHO EURO Statement: More than half of WHO European Region experiencing intense, early influenza season driven by new strain) and the latest FluView data (which is at least 2 weeks old at this point), attest to its impact. 

Whether we'll experience the same protracted flu season as has Australia remains to be seen - but it is certainly possible - making it still very much worth getting this year's flu vaccine if you haven't already. 

Despite concerns that this year's vaccine may not be as effective against this drifted subclade; it is still expected to provide valuable protection against severe disease (see UKHSA Preprint: Early Influenza Virus Characterisation and Vaccine Effectiveness in England in Autumn 2025, A Period Dominated by Influenza A(H3N2) Subclade K)

How much protection?  Well, we probably won't have good data until later this month, and the full story won't be known until next summer.  But anything that reduces your chances of being hospitalized with severe influenza has value. 

Which is why I also wear a mask in public, use copious amounts of hand sanitizer, and try to avoid crowded indoor spaces.  A strategy which has helped keep me respiratory illness free for nearly 5 years.  

Last year was pegged as being the worst flu season in nearly a decade (see MMWR: Influenza-Associated Hospitalizations During a High Severity Season (United States, 2024–25)), but this year could end up being even more challenging.

 

Already New York state is reporting a faster start to this year's flu season (see dashboard below) and last week their DOH reported (New York State Department of Health Confirms Most Flu Cases Ever Recorded in One Week).

While many people trivialize the flu, numerous studies suggest strong links between influenza infection and cardiovascular events like heart attacks and strokes (see also Eur. Resp.J.: Influenza & Pneumonia Infections Increase Risk Of Heart Attack and Stroke).

In early 2023, in Neuron: Virus Exposure and Neurodegenerative Disease Risk Across National Biobanks, we also looked at a study published in Cell Neuron which found a statistical linkage between viral illnesses and developing neurodegenerative diseases later in life.

And every once in a while seasonal flu will serve us up a curveball, sometimes even in the middle of the season.  A few examples:

• In 2008, H1N1 abruptly developed nearly 100% resistance to oseltamivir;
• In 2014, we saw a late summer mutation appear in the H3N2 virus (see HAN Advisory On `Drifted’ H3N2 Seasonal Flu Virus) which greatly reduced the effectiveness of that year's flu vaccine.
• in 2016, we saw warnings over mutated (D225G) H1N1 viruses in Russia and in Europe (see ECDC Risk Assessment : Reports Of Severe A(H1N1)pdm09 In Europe);
• And while it has had only limited impact so far, we are now watching another slow rise in antiviral resistance in H1N1

But the biggest seasonal flu aberration may well have been the Liverpool Flu of 1951, which - for about six weeks - caused a virulent flu virus to spread across the UK and into Canada was as deadly as the 1918 pandemic.

This graphic comes from the March 16th, 1951 Proceedings of The Royal Society of Medicine – page 19 – and shows in detail the tremendous spike in influenza deaths in early 1951 over the (admittedly, unusually mild) 1948 flu season.  

In 2006 the CDC's EID Journal published a stellar account of this event, and it is very much worth reading. 

Viboud C, Tam T, Fleming D, Miller MA, Simonsen L. 1951 influenza epidemic, England and Wales, Canada, and the United States. Emerg Infect Dis [serial on the Internet]. 2006 Apr [date cited].

A sobering reminder that even seasonal flu deserves our respect. 

Nature: Respiratory Viral Infections Awaken Metastatic Breast Cancer Cells in Lungs

 

#18,880

While most people consider influenza and (now) COVID to be a relatively minor, self-limiting, infections - and vaccine uptake for both have fallen - we continue to see evidence of their often devastating extrapulmonary impact. 

European Society of Cardiology: Major Consensus Statement Released on Long-Term Cardiovascular Impact of COVID Infection

BMC Neurology: Long-term Neurological and Cognitive Impact of COVID-19: A Systematic Review and Meta-analysis in over 4 Million Patients

Risk of Cardiovascular Events After Influenza: A Population-based Self Controlled Case Series Study

Nature: Severe Influenza in Pregnancy Linked to Neurodevelopmental Disorders in Offspring

Eur. Resp.J.: Influenza & Pneumonia Infections Increase Risk Of Heart Attack and Stroke

While all of this is more than enough to inspire me to get the flu/COVID shot every year -  for anyone desirous of additional motivation - we have a recent (July 2025) report in Nature which suggests that respiratory infections can activate dormant cancers (at least, in mice). 

The abstract from the study, and an NIH press release, follow.  I'll have a bit more after the break.

Article
Open access
Published: 30 July 2025
Respiratory viral infections awaken metastatic breast cancer cells in lungs

Shi B. Chia, Bryan J. Johnson, Junxiao Hu, Felipe Valença-Pereira, Marc Chadeau-Hyam, Fernando Guntoro, Hugh Montgomery, Meher P. Boorgula, Varsha Sreekanth, Andrew Goodspeed, Bennett Davenport, Marco De Dominici, Vadym Zaberezhnyy, Wolfgang E. Schleicher, Dexiang Gao, Andreia N. Cadar, Lucia Petriz-Otaño, Michael Papanicolaou, Afshin Beheshti, Stephen B. Baylin, Joseph W. Guarnieri, Douglas C. Wallace, James C. Costello, Jenna M. Bartley, …
James DeGregori Show authors

Nature

Abstract

Breast cancer is the second most common cancer globally, with most deaths caused by metastatic disease, often following long periods of clinical dormancy1. Understanding the mechanisms that disrupt the quiescence of dormant disseminated cancer cells (DCCs) is crucial for addressing metastatic progression. Infections caused by respiratory viruses such as influenza and SARS-CoV-2 trigger both local and systemic inflammation2,3. 

Here we demonstrate, in mice, that influenza and SARS-CoV-2 infections lead to loss of the pro-dormancy phenotype in breast DCCs in the lung, causing DCC proliferation within days of infection and a massive expansion of carcinoma cells into metastatic lesions within two weeks. These phenotypic transitions and expansions are interleukin-6 dependent. We show that DCCs impair lung T cell activation and that CD4+ T cells sustain the pulmonary metastatic burden after the influenza infection by inhibiting CD8+ T cell activation and cytotoxicity. Crucially, these experimental findings align with human observational data. 

Analyses of cancer survivors from the UK Biobank (all cancers) and Flatiron Health (breast cancer) databases reveal that SARS-CoV-2 infection substantially increases the risk of cancer-related mortality and lung metastasis compared with uninfected cancer survivors. 

These discoveries underscore the huge impact of respiratory viral infections on metastatic cancer resurgence, offering new insights into the connection between infectious diseases and cancer metastasis.

        (Continue . . . )

August 19, 2025
Respiratory viruses may trigger dormant cancers

At a Glance

•  A study in mice showed how common respiratory viruses may awaken dormant cancer cells.  

• The findings suggest these viruses can pose additional risks for people with a history of cancer.

Respiratory viruses could awaken dormant cancer cells in the lungs.

CI Photos / Shutterstock

Cancer cells can break away from their original tumors and travel to different parts of the body. These disseminated cancer cells (DCCs) can then grow into new tumors. This process is called metastasis. DCCs can stay dormant for years or decades before awakening and developing into tumors, even long after the original tumor is removed. What causes the cells to awaken has been unknown.

Studies have shown that cancer metastasis can be triggered by inflammation. Infection by respiratory viruses, such as influenza and SARS-CoV-2, often causes inflammation. A research team led by Dr. James DeGregori at the University of Colorado Anschutz Medical Campus set out to test whether respiratory virus infections might cause DCCs to awaken. To do this, they used mouse models of breast cancer to study the effects of influenza and SARS-CoV-2 infection on DCCs and metastasis in the lungs. The study appeared in Nature on July 30, 2025.

Before infection, the mice’s lungs contained only a small number of isolated DCCs. Within three days of infection with influenza virus, the lungs had a striking increase in number of DCCs. This number continued to grow over the course of two weeks and remained elevated even 9 months after infection. The increase in DCCs was accompanied by a decline in the share of DCCs that were in a dormant state. Similar effects were seen in mice infected with SARS-CoV-2.

Further experiments showed that the virus-induced awakening of DCCs required the inflammatory signaling molecule IL-6. Mice that couldn’t produce IL-6 had much less DCC growth and a greater share of dormant DCCs in their lungs after influenza infection. Moreover, organoids formed from the mice’s mammary glands grew significantly when treated with IL-6.

The team noted that DCCs tended to cluster near immune cells called CD4+ T cells. Depleting CD4+ T cells reduced the number of DCCs that were still awake one month after infection. It also increased the number of CD8+ T cells, which kill cancer and virus-infected cells, in the lungs. CD8+ T cells in CD4+ T cell-depleted mice were more effective at killing breast cancer cells. This suggests that CD4+ T cells aid awakened DCCs by suppressing CD8+ T cell activity.

The team next looked at the association between SARS-CoV-2 infection and cancer progression and mortality in electronic health records. They examined data from the UK Biobank on almost 5,000 people who had a prior cancer diagnosis and were inferred to be in remission.

Among this population, a positive test for SARS-CoV-2 nearly doubled the risk of death from cancer. In a separate dataset of more than 36,000 women with breast cancer, having COVID-19 increased the risk of metastasis to the lungs by about 40%.

The findings suggest how respiratory virus infections may contribute to the risk of cancer recurrence and metastasis. They also point to potential targets for interventions that could reduce this risk.

“Dormant cancer cells are like the embers left in an abandoned campfire, and respiratory viruses are like a strong wind that reignites the flames,” DeGregori explains.

—by Brian Doctrow, Ph.D.

We are coming off one of the worst flu seasons in more than a decade (see
MMWR: Influenza-Associated Hospitalizations During a High Severity Season (United States, 2024–25)).

 

While we can't predict what this fall/winter respiratory season will bring, Dr. Ian Mackay has reported repeatedly on Australia's high-impact flu season the past few months (see A Flunami in July).

Which is why, sometime in the next couple of weeks,  I'll roll up my sleeve to get my 20th seasonal flu shot in as many years.

I recognize it probably only provides my age group with 30%-40% protection.

 

But given the long list of things that can go wrong during or following flu infection, I'll take whatever advantage I can get. 

Nature: Severe Influenza in Pregnancy Linked to Neurodevelopmental Disorders in Offspring

Photo Credit – CDC 

#18,215

While most people tend to regard the flu as a nasty, but relatively trivial and self-limiting, respiratory infection, it is obvious that for some high risk groups - including children, the elderly, the immunocompromised, and those who are pregnant - influenza can have profound and lasting impacts. 

Studies suggest strong links between influenza infection and cardiovascular events like heart attacks and strokes (see also Eur. Resp.J.: Influenza & Pneumonia Infections Increase Risk Of Heart Attack and Stroke).

And we've seen evidence suggesting that repeated influenza infections may be linked to an increase risk of developing Parkinson's later in life (see 2017's Nature Comms: Revisiting The Influenza-Parkinson's Link). 

In early 2023, in Neuron: Virus Exposure and Neurodegenerative Disease Risk Across National Biobanks, we also looked at a study published in Cell Neuron which found a statistical linkage between viral illnesses and developing neurodegenerative diseases later in life.

Many studies have found links between maternal influenza infection and damage to the unborn child, as in last January's CIMB Review: Maternal Influenza and Offspring Neurodevelopment).

Historical accounts and studies following the last four influenza pandemics (1918, 1957, 1968, and 2009) all showed distinct increases in maternal mortality, the number stillbirths, and evidence of impaired fetal development. 

The best records come from the most recent, and mildest, of these flu pandemics (2009).  

• In 2011, in BMJ: Perinatal Outcomes After Maternal 2009/H1N1 Infection a study found pregnant women who were admitted to the hospital with an H1N1 infection experienced a 3 to 4 times higher rate of preterm birth, 4 to 5 times greater risk of stillbirth, and a 4 to 6 times higher rate of neonatal death.
• And in 2019, Study: Outcomes Of Infants Born To Women With Influenza A(H1N1)pdm09 found that women admitted to the ICU with H1N1 were more likely to deliver preterm infants, low birth weight infants, and infants with low Apgar scores than women in the other groups.

We've also seen studies that have attempted to quantify the impact of influenza infection on both pregnant women and their offspring. While some of these studies are more compelling than others, we've seen a wide spectrum of sequelae linked to maternal flu infection, including:

Pregnancy, Influenza & Elevated Psychosis Risks In Adult Offspring

Molecular Psy.: Increased Autism Risk Linked To Prenatal Fever

JAMA Psych: Long-term Risk of Neuropsychiatric Disease After Exposure to Infection In Utero

Systematic Review & Meta-Analysis: First-Trimester Influenza Infection Increases the Odds of Non-Chromosomal Birth Defects

This week the Journal Nature has published another study, this time conducted using live mouse-adapted influenza virus and pregnant lab mice, which finds it is the mothers immune response to the virus that causes damage to the unborn offspring. 

This is a lengthy, and highly technical, report so I've just reproduced the link, and abstract, along with some excerpts from a press release from the University of Illinois.  Follow the links to read them in their entirety, I'll have a brief postscript after the break. 

Influenza A virus during pregnancy disrupts maternal intestinal immunity and fetal cortical development in a dose- and time-dependent manner

Ashley M. Otero, Meghan G. Connolly, Rafael J. Gonzalez-Ricon, Selena S. Wang, Jacob M. Allen & Adrienne M. Antonson 
Molecular Psychiatry (2024)Cite this article

Abstract

Epidemiological studies link exposure to viral infection during pregnancy, including influenza A virus (IAV) infection, with increased incidence of neurodevelopmental disorders (NDDs) in offspring.

Models of maternal immune activation (MIA) using viral mimetics demonstrate that activation of maternal intestinal T helper 17 (TH17) cells, which produce effector cytokine interleukin (IL)-17, leads to aberrant fetal brain development, such as neocortical malformations. Fetal microglia and border-associated macrophages (BAMs) also serve as potential cellular mediators of MIA-induced cortical abnormalities. However, neither the inflammation-induced TH17 cell pathway nor fetal brain-resident macrophages have been thoroughly examined in models of live viral infection during pregnancy. 

Here, we inoculated pregnant mice with two infectious doses of IAV and evaluated peak innate and adaptive immune responses in the dam and fetus. While respiratory IAV infection led to dose-dependent maternal colonic shortening and microbial dysregulation, there was no elevation in intestinal TH17 cells nor IL-17. Systemically, IAV resulted in consistent dose- and time-dependent increases in IL-6 and IFN-γ. Fetal cortical abnormalities and global changes in fetal brain transcripts were observable in the high-but not the moderate-dose IAV group. Profiling of fetal microglia and BAMs revealed dose- and time-dependent differences in the numbers of meningeal but not choroid plexus BAMs, while microglial numbers and proliferative capacity of Iba1+ cells remained constant. Fetal brain-resident macrophages increased phagocytic CD68 expression, also in a dose- and time-dependent fashion. 

Taken together, our findings indicate that certain features of MIA are conserved between mimetic and live virus models, while others are not. Overall, we provide consistent evidence of an infection severity threshold for downstream maternal inflammation and fetal cortical abnormalities, which recapitulates a key feature of the epidemiological data and further underscores the importance of using live pathogens in NDD modeling to better evaluate the complete immune response and to improve translation to the clinic.

         (Continue . . . )

 

Fetal brain impacted when mom fights severe flu: New mouse study explains how

Peer-Reviewed Publication

UNIVERSITY OF ILLINOIS COLLEGE OF AGRICULTURAL, CONSUMER AND ENVIRONMENTAL SCIENCES

URBANA, Ill. -- A bad case of the flu during pregnancy can increase the risk for fetal neurodevelopmental disorders such as schizophrenia and autism spectrum disorder. But it’s not the virus itself doing the damage; it’s the mother’s immune response.

New University of Illinois Urbana-Champaign research using live mouse-adapted influenza virus improves upon previous mouse experiments to explain the process on a cellular and molecular level. It also indicates fetal brain changes are more likely once the severity of the mother’s infection meets a specific threshold.

“Our data provide really compelling evidence for an infection severity threshold, which mimics what we see in humans. There are only a subset of maternal infections that are going to be severe enough to cause concerns like this. That said, pregnant people should definitely get the flu vaccine to reduce their risk,” said senior study author Adrienne Antonson, assistant professor in the Department of Animal Sciences, part of the College of Agricultural, Consumer and Environmental Sciences at Illinois.

The study is one of only a handful to investigate maternal infection in mice using live influenza virus at doses that replicate seasonal flu outbreaks in humans. “That means our results are more relevant to human pathological infection,” said lead study author Ashley Otero, a doctoral student in the Neuroscience Program at Illinois.

Antonson’s team infected pregnant mice with live influenza A virus, rather than a viral mimic — an inert molecule that mimics viral behavior — used by most research groups in recent decades. The viral mimic elicits the innate immune response, broadly categorized as non-specific inflammation, that occurs within 24 to 48 hours of infection.

These studies have provided important clues about which inflammatory proteins are made by the mother and how they interact with the fetal brain. But Otero says viral mimics may prompt slightly different immune responses than the live virus in both mother and fetus, and they fail to capture what happens during the mother’s adaptive immune response, which occurs later and helps an animal “remember” past infections.

To address these issues, the team subjected the mice to one of two doses of the virus — representing a moderate or severe infection — at the moment in gestation closest to the end of the first trimester in humans. Then, at two and seven days post-infection, they tracked how the infection progressed in the lungs and intestines of the mother, as well as how products from the mother’s immune response interacted with the fetal brain. They also measured the physical properties of fetal brains, including the thickness of the cortex, which has been linked to neurodevelopmental disorders in humans.

(SNIP)

Antonson emphasizes that maternal infection is only one of many risk factors for neurodevelopmental disorders.

“These disorders are caused by a multitude of elements, including environmental factors, genetics, pharmacological exposures, and more. We're focusing on just this in-utero period, but the early postnatal period is important, and adolescence is important. It’s just one slice of a very complicated pie.”

The study, “Influenza A virus during pregnancy disrupts maternal intestinal immunity and fetal cortical development in a dose- and time-dependent manner,” is published in Molecular Psychiatry [DOI: 10.1038/s41380-024-02648-9]. The research was supported by the Roy J. Carver Charitable Trust (grant #23-5683), USDA NIFA Research Capacity Fund (Hatch project #ILLU-538-940), the Department of Animal Sciences, and the College of ACES.

Antonson is also affiliated with the Beckman Institute, the Microbial Systems Initiative, and the Carl R. Woese Institute for Genomic Biology at Illinois.

This study adds to the growing list of evidence that influenza (and other viral infections) can sometimes have a profound, and long-term, impact on the host. 

At the same time we've seen many studies confirming the safety and benefits of flu vaccination and the early use of antivirals in protecting the lives of pregnant women and their unborn child, including:

Pediatrics: Maternal Flu Vaccination Extends Protection To Infants

Clinical Infectious Diseases: Flu Vaccine May Reduce Incidence of Stillbirth

JID: Benefits Of Early Use of Influenza Antivirals In Pregnancy

While seasonal flu vaccines only provide moderate protection against infection, they do a much better job at reducing the severity of the illness (see CDC MMWR: Interim 2023-2024 Flu Vaccine Effectiveness Estimates).  

And as this study points out, the risks to the unborn child go up with the severity of the maternal infection. If you can reduce the severity, you should also reduce the chances of neurodevelopmental disorders.

While there is no doubt we need better seasonal flu vaccines, even a little protection can make the difference between a mild, self-limiting illness, and something much worse. 

CDC Updates & Revises RSV, COVID & Flu Vaccination Recommendations for Fall 2024

Credit ACIP/CDC 

#18,155

This week, following advice from ACIP (The Advisory Committee on Immunization Practices) the CDC has released updated recommendations for RSV, COVID, and seasonal flu vaccinations.  

As we noted at the end of May (see MMWR: Early Safety Findings Among Persons Aged ≥60 Years Who Received a RSV Vaccine — United States, May 3, 2023–April 14, 2024) there are some concerns over a higher-than-expected incidence of GBS (Guillain-Barré syndrome) among those who received this recent addition to the vaccine lineup.

The spike wasn't huge, and given the heavy impact of RSV infection on the elderly, pending more information, the advice from the CDC remained: 

RSV vaccination continues to be recommended for adults aged ≥60 years using shared clinical decision-making (9). CDC and FDA are conducting active safety evaluations to assess risks for GBS and other adverse events of special interest after RSV vaccination.

This week's recommendation scales back the recommendation for those aged 60-74, to those ` . . . who are at increased risk of severe RSV, meaning they have certain chronic medical conditions, such as lung or heart disease, or they live in nursing homes . . .'

The announcement from the CDC follows:

CDC Updates RSV Vaccination Recommendation for Adults

For the upcoming respiratory virus season, CDC recommends everyone age 75 and older receive the RSV vaccine

Media Statement

For Immediate Release, Wednesday, June 26, 2024
Contact: Media Relations
(404) 639-3286
media@cdc.gov


Today, CDC updated its recommendation for the use of Respiratory Syncytial Virus (RSV) vaccines in people ages 60 and older. For this upcoming respiratory virus season, CDC recommends:

• Everyone ages 75 and older receive the RSV vaccine.

• People ages 60–74 who are at increased risk of severe RSV, meaning they have certain chronic medical conditions, such as lung or heart disease, or they live in nursing homes, receive the RSV vaccine.

This recommendation is for adults who did not get an RSV vaccine last year. The RSV vaccine is not currently an annual vaccine, meaning people do not need to get a dose every RSV season. Eligible adults can get an RSV vaccine at any time, but the best time to get vaccinated is in late summer and early fall before RSV usually starts to spread in communities.

Today’s updated recommendation for people 60 and older replaces the recommendation made last year to simplify RSV vaccine decision-making for clinicians and the public.

Immunizations were available last year for the first time to protect people at increased risk for severe RSV, including infants and young children, and people ages 60 and older. Today’s updated recommendation is based on analyses of RSV disease burden among people 60 and older, as well as RSV vaccine effectiveness and cost-effectiveness studies. Those studies included the first real-world data since RSV vaccines were recommended for people 60 and older.

Healthcare providers should recommend RSV vaccines to their eligible patients, as well as discuss what other vaccines they will need this fall to help prevent respiratory infections.

The following is attributable to CDC Director Dr. Mandy Cohen:

“The CDC has updated its RSV vaccination recommendation for older adults to prioritize those at highest risk for serious illness from RSV,” said Mandy Cohen, M.D., M.P.H. “People 75 or older, or between 60-74 with certain chronic health conditions or living in a nursing home should get one dose of the RSV vaccine to provide an extra layer of protection.”

The advice this year for receiving both the flu and COVID vaccines is basically unchanged, although for the first time in a decade the quadrivalent vaccine will not be offered as they B/Yamagata strain has not been seen in 4 years. 

The CDC reports that COVID continues to claim more lives than influenza in the United States (75,500 in 2023).  Two weeks ago the FDA Updated COVID Vaccine Recommendations: Use KP.2 Strain If Feasible, due to its constant and rapid evolution. 

The full CDC announcement follows, I'll have a brief postscript after the break. 

CDC Recommends Updated 2024-2025 COVID-19 and Flu Vaccines for Fall/Winter Virus Season
 
Media Statement

For Immediate Release: June 27, 2024
Contact: Media Relations
(404) 639-3286

Today, CDC recommended the updated 2024-2025 COVID-19 vaccines and the updated 2024-2025 flu vaccines to protect against severe COVID-19 and flu this fall and winter.

It is safe to receive COVID-19 and flu vaccines at the same visit. Data continue to show the importance of vaccination to protect against severe outcomes of COVID-19 and flu, including hospitalization and death. In 2023, more than 916,300 people were hospitalized due to COVID-19 and more than 75,500 people died from COVID-19. During the 2023-2024 flu season, more than 44,900 people are estimated to have died from flu complications.

Updated 2024-2025 COVID-19 Vaccine Recommendation

CDC recommends everyone ages 6 months and older receive an updated 2024-2025 COVID-19 vaccine to protect against the potentially serious outcomes of COVID-19 this fall and winter whether or not they have ever previously been vaccinated with a COVID-19 vaccine. Updated COVID-19 vaccines will be available from Moderna, Novavax, and Pfizer later this year. This recommendation will take effect as soon as the new vaccines are available.

The virus that causes COVID-19, SARS-CoV-2, is always changing and protection from COVID-19 vaccines declines over time. Receiving an updated 2024-2025 COVID-19 vaccine can restore and enhance protection against the virus variants currently responsible for most infections and hospitalizations in the United States. COVID-19 vaccination also reduces the chance of suffering the effects of Long COVID, which can develop during or following acute infection and last for an extended duration.

Last season, people who received a 2023-2024 COVID-19 vaccine saw greater protection against illness and hospitalization than those who did not receive a 2023-2024 vaccine. To date, hundreds of millions of people have safely received a COVID-19 vaccine under the most intense vaccine safety monitoring in United States history.

Updated 2024-2025 Flu Vaccine Recommendation

CDC recommends everyone 6 months of age and older, with rare exceptions, receive an updated 2024-2025 flu vaccine to reduce the risk of influenza and its potentially serious complications this fall and winter. CDC encourages providers to begin their influenza vaccination planning efforts now and to vaccinate patients as indicated once 2024-2025 influenza vaccines become available.

Most people need only one dose of the flu vaccine each season. While CDC recommends flu vaccination as long as influenza viruses are circulating, September and October remain the best times for most people to get vaccinated. Flu vaccination in July and August is not recommended for most people, but there are several considerations regarding vaccination during those months for specific groups:

• Pregnant people who are in their third trimester can get a flu vaccine in July or August to protect their babies from flu after birth, when they are too young to get vaccinated. 

Children who need two doses of the flu vaccine should get their first dose of vaccine as soon as it becomes available. The second dose should be given at least four weeks after the first.

Vaccination in July or August can be considered for children who have health care visits during those months if there might not be another opportunity to vaccinate them.
For adults (especially those 65 years old and older) and pregnant people in the first and second trimester, vaccination in July and August should be avoided unless it won’t be possible to vaccinate in September or October.

Updated 2024-2025 flu vaccines will all be trivalent and will protect against an H1N1, H3N2 and a B/Victoria lineage virus. The composition of this season’s vaccine compared to last has been updated with a new influenza A(H3N2) virus.

For more information on updated COVID-19 vaccines visit: Coronavirus Disease 2019 (COVID-19) | CDC. For more information on updated flu vaccines visit: Seasonal Flu Vaccines | CDC.

The following statement is attributable to CDC Director Dr. Mandy Cohen:

“Our top recommendation for protecting yourself and your loved ones from respiratory illness is to get vaccinated,” said Mandy Cohen, M.D., M.P.H. “Make a plan now for you and your family to get both updated flu and COVID vaccines this fall, ahead of the respiratory virus season.”

Studies suggest strong links between influenza infection and cardiovascular events like heart attacks and strokes (see also Eur. Resp.J.: Influenza & Pneumonia Infections Increase Risk Of Heart Attack and Stroke).

And we've seen evidence suggesting that repeated influenza infections may be linked to an increase risk of developing Parkinson's later in life (see 2017's Nature Comms: Revisiting The Influenza-Parkinson's Link). 

In early 2023, in Neuron: Virus Exposure and Neurodegenerative Disease Risk Across National Biobanks, we also looked at a study published in Cell Neuron which found a statistical linkage between viral illnesses and developing neurodegenerative diseases later in life.

At an AAIC Meeting in 2020 (see Flu & Pneumonia Shots Appear To Reduce Dementia Risk In Elderly, researchers presented evidence suggesting:

● At least one flu vaccination was associated with a 17% reduction in Alzheimer’s incidence. More frequent flu vaccination was associated with another 13% reduction in Alzheimer’s incidence.

● Vaccination against pneumonia between ages 65 and 75 reduced Alzheimer’s risk by up to 40% depending on individual genes. 

While the current flu vaccine is nowhere near as effective as we'd like it to be, and the promise of a universal flu vaccine remains elusive (see  J.I.D.: NIAID's Strategic Plan To Develop A Universal Flu Vaccine), there is growing evidence to suggest the benefits of vaccination may extend beyond simply reducing the risk of influenza infection. 

I view getting a yearly flu shot like always wearing a seat belt in an automobile. It doesn't guarantee a good outcome in a car wreck, but it certainly increases your odds of walking away. 

 

Which is why I'll be rolling up my sleeve this fall for both the Flu and COVID vaccines.  Because at my age - and in my physical condition - I can use all the advantages I can get.