We are all very familiar now with the way viral infections lead to acute disease. From the flu to COVID-19 and the measles, it is well understood how viruses lead to disease but scientists are only now discovering the broad role viral infections play in the development of other health conditions, often emerging years or even decades after the initial infection.

Several new studies have shed light on links between diseases not previously thought to be related to viral infections. A common childhood viral infection has been linked to the development of bladder cancer in adulthood. An association between hepatitis C and schizophrenia is offering insights into the influence of viral infections on the brain. And strong new evidence is affirming how a prevalent virus may be crucial to the development of multiple sclerosis.

Cancer and viruses

It has been estimated that nearly one in five cancers worldwide are caused by viral infections. Perhaps the most well known viral cancer connection is the link between cervical cancer and HPV (human papillomavirus).

Nearly all cases of cervical cancer are thought to be caused by HPV. Over the last decade vaccines against HPV have improved, raising the prospect of virtually eliminating cervical cancer in the future and saving hundreds of thousands of lives every year.

A new study, published in the Nature journal Oncogene and led by researchers from the University of York, has discovered a new link between bladder cancer and infection with a common virus. The virus is known as BK (BK polyomavirus), and up to 80 percent of people have caught the virus by the time they reach adulthood. For most people BK infections are asymptomatic but the virus can remain dormant inside the body for decades, particularly in the kidneys.

Based on this understanding, the researchers investigated whether there is a potential mechanism by which this persistent BK infection in the kidney could trigger the onset of bladder cancer. Through a series of in vitro experiments the researchers found BK infections lead the kidney to produce anti-viral enzymes called APOBECs.

When dormant BK infections in the kidney reactivate, the immune system produces APOBECs to kill the virus. However, these specialist immune cells can move to the bladder and subsequently damage DNA in bladder cells.

This process can repeatedly occur for decades before bladder cancer appears and is diagnosed. And, by the time the cancer appears there is often no sign of BK virus as it is either dormant or has been completely eliminated by the immune system. The only sign of this relationship is mutational signatures of APOBEC in the genome of bladder tumor cells.

“Our findings alter our understanding of the causes of bladder cancer by showing that BK virus infections are a risk factor for bladder cancer because they force bladder cells to use APOBECs that damage their DNA,” said Simon Baker, lead author on the study.

The researchers note APOBEC signatures can be found in around 93 percent of all bladder cancers, affirming the hypothesis these tumors are triggered by dormant viral infections. The new findings may also help explain why immunosuppressed renal transplant patients experience significantly high rates of bladder cancer.

It’s early days but Baker calls for the development of a BK vaccine. He says it is possible such a vaccine could have the same impact on bladder cancer as HPV vaccines have had on cervical cancer.

“This research is critically needed to improve our understanding of why people who are immunosuppressed, such as transplant patients, get more bladder cancers,” said Baker. “Our research should not only help improve the care we give to these patients, but it may also have much wider implications for preventing bladder cancer in the future.”

Schizophrenia and viruses

Over the last couple of decades several observational studies have looked at the relationship between hepatitis C (HCV) infections and schizophrenia. The data so far has been decidedly discordant, with some studies having found significantly higher rates of hep C in patients with schizophrenia, while others have found the connection inconsistent and non-significant.

A new study from researchers in Taiwan has looked at millions of health records to not only analyze the prevalence of schizophrenia in hepatitis C positive subjects but to also compare rates of schizophrenia in HCV patients treated with interferon-based therapy. The hypothesis was that if HCV infection precedes, and thus is a cause of, schizophrenia, then effective early treatment of the viral infection should reduce a person’s chances of developing the mental illness.

The findings revealed a significantly higher prevalence of schizophrenia in the cohort of untreated HCV patients (0.87 percent) compared to those treated for HCV (0.25 percent) and those not infected with HCV in the first place (0.11 percent).

The researchers are cautious to make it very clear schizophrenia is a complex and highly heritable condition. So the development of schizophrenia will always involve a number of genetic and environmental factors beyond just a single viral infection.

Nevertheless, the researchers hypothesize several plausible mechanisms by which HCV infection could influence the initiation of schizophrenia. And considering there are antiviral agents available to treat HCV infection it may be worthwhile to consider future complications, such as increased risk of schizophrenia, when considering potential antiviral treatments.

“In the era of DAAs [direct-acting antivirals] to eliminate HCV infection, anti-HCV therapy should be prescribed for all people infected with HCV to reduce the risk not only of hepatic complications, but also of extrahepatic complications, including schizophrenia,” the study concludes.

Neurodegeneration, dementia and viruses

The hypothesis linking neurodegenerative disease with viral infection has been around for nearly a century. The idea of “slow virus diseases”, viral infections that result in the progressive destruction of neurological processes, goes back to the mid-20th century, with many scientists suggesting persistent herpes infections were the cause of Alzheimer’s disease.

These ideas lost their popularity in the late-20th century as other causal hypotheses for diseases such as Alzheimer’s gained prominence. But more recently researchers have turned back to this old idea after the failure of drugs designed to target other pathological signs of neurodegenerative disease.

Perhaps the strongest recent body of study on neurodegenerative disease and viral infection has come from researchers investigating the relationship between multiple sclerosis and the Epstein-Barr virus. Several observational studies over the past few years have pointed to strong correlations between viral infections in a person’s teenage years and the subsequent development of MS around a decade later.

A recent study published in the journal Science offered some of the most compelling causal evidence of that connection to date. Led by researchers from the Harvard T.H. Chan School of Public Health, the study looked at a unique dataset of health records from members of the US military. The data offered over 20 years of information, allowing the researchers to understand whether infection with the Epstein-Barr virus (EBV) preceded the development of MS.

The results affirmed all cases of MS were preceded by EBV infections. The median time from EBV infection to onset of MS was 7.5 years but some people developed MS as soon as two years after an EBV infection, while others didn’t develop it for as long as 15 years. No other viral infection was seen to so consistently link with MS development.

Much like the schizophrenia research, there is no claim that EBV infection is the sole cause of MS. Again, there are plenty of other factors that contribute to development of MS. After all, EBV infection is very prevalent in young people, so if everyone infected with the virus ended up with MS we would surely know it.

Instead, the findings indicate it is likely that EBV infections are a big factor in triggering MS for those already susceptible to the disease. The current working hypothesis is that not all people infected with EBV will develop MS, but all those who develop MS are likely to have been previously infected with EBV.

And perhaps most importantly, if EBV is a fundamental trigger for the disease in most people then a vaccine against EBV could hypothetically eradicate MS. Several biotech companies have recently announced EBV vaccines are in the pipeline.

It’s early days for many of these research pathways investigating the relationship between viral infections and chronic diseases but it is becoming increasingly clear we may have underestimated the long-term effects of acute viral infections. From Alzheimer’s to cancer there are plausible hypotheses suggesting these terrible diseases could be prevented by vaccines targeting viruses previously assumed to be relatively harmless.