An interesting new study shows that several viruses, including influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), significantly affect secondary infection or coinfection with other pathogens. The study reveals that multiple pathogens can be monitored simultaneously in this way, allowing cost-effective data to be collected for coinfection studies while also adding richness to the clinical and epidemiological context of the data.
Study: Interactions among 17 respiratory pathogens: a cross-sectional study using clinical and community surveillance data. Image Credit: creativeneko/Shutterstock
Introduction
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Many different viruses and bacteria inhabit the human respiratory tract, many being commensal and some pathogenic. They compete to use available resources, exploit chinks in host immunity and generally adapt to their environment or make it adapt to them. In addition, they block or promote the replication of other species, which may significantly alter the host response to infection. This phenomenon, called coinfection, is thus both clinically relevant and epidemiologically important.
In most cases, coinfection by a virus and a bacterium favors the proliferation of the bacterium, but when two viruses are present, they tend to inhibit each other. This explains why many patients with influenza show the presence of Streptococcus pneumonia (Pneumococcus), or higher colony counts than before, as also occurs following other respiratory virus infections.
Most data on these interactions come from laboratories, animal studies, and modeling studies. The new study, available on the medRxiv* preprint server, uses polymerase chain reaction (PCR) data on 17 different pathogens, collected from clinical samples as part of the Seattle Flu Study, a community-based surveillance study of respiratory viral infections. The researchers aimed to build a database that avoided collider bias, which can occur when infection-naïve samples are not part of the study. Thus the relative risk is falsely low.
What did the study show?
The scientists obtained almost 21,700 positive samples from 27,400 cases of infection. Over half were from hospital residual specimens, and one in three were from community testing. One in seven came from outpatient testing.
The most common pathogen was human rhinovirus, found in over a third of the samples, and pneumococcus, in about 30%. SARS-CoV-2, the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic, was found in slightly less than one in seven cases, with influenza A H1N1 and influenza B viruses accounting for less than 10% each.
In more than three-quarters of positive samples, only a single pathogen was detected. In about a fifth, there were two, while three or four co-pathogens were found in a small minority. Rhinovirus-pneumococcal coinfections were the most common in about 7% of all positive samples, while pneumococcus was detected along with adenovirus and respiratory syncytial virus A (RSV-A) in approximately 2% each.
In most of these cases, pneumococcus benefited from the coinfection, as shown by the rise in bacterial load.
The scientists failed to find any virus-virus interaction with facilitation of infection by one pathogen being brought about by the other – as evidenced by a higher viral load of one pathogen of the two, compared to a single infection by the same pathogen. Conversely, in many cases, interference or competition was suggested by the reduced viral load of the viruses in the coinfection pairs.
These results corroborate earlier findings. However, the results show that the influenza A and B viruses are the most powerful inhibitors of coinfecting viruses, with significant effects being observed in 14 of the 21 pairs of viruses that provided adequate data. In contrast, other viruses did not appear to exert an inhibitory effect on the influenza viruses. This unidirectional suppressive effect on viral proliferation seems to be mediated by host immune responses elicited by the influenza virus, such that succeeding viruses are blocked to a large extent.
Other researchers have shown that a history of coronavirus infection failed to affect the chances of getting the flu. Still, the opposite effect was observed if the flu came first, with subsequent coronavirus infection suppressed. Effective influenza vaccines could mean that other respiratory virus infections will shift away from the current trends.
Pneumococcal infection can become systemic or invasive in the lower respiratory tract, causing severe or critical disease. However, its primary site of infection, in the upper respiratory mucosa, is amenable to asymptomatic carriage. With influenza A infection, the bacteria tend to adhere more tightly, colonize and invade the mucosa, causing illness and higher rates of bacterial shedding from the mucosa, which promotes the spread of the pathogen.
Throughout the current pandemic, pneumococcal density was higher with viral coinfections, whether at the individual patient or population levels. However, influenza A is among the weakest facilitators of pneumococcal infection, perhaps because it suppresses other viruses since pneumococcal density is highest when more viruses are present.
No virus appeared to be able to increase the degree of facilitation of pneumococcal infection by influenza A virus, a finding that goes against some recent reports.
Interestingly, rhinovirus infection was suppressed by SARS-CoV-2, another finding that is in discordance with recent studies that reported rhinoviruses elicited an innate immune response that inhibited the former. On the other hand, the current study did show that human seasonal endemic coronaviruses did show inhibition with rhinovirus coinfection.
This is thought to be due to pre-existing immunity to one or more of the five human seasonal coronaviruses, which is more unlikely with rhinoviruses since there are hundreds of them circulating at an endemic level. Secondly, adaptive immunity may reduce the peak viral load, reducing the chances that human seasonal coronaviruses could interfere with rhinovirus replication.
If this is true, rhinovirus coinfection may mitigate SARS-CoV-2 virus in the future.
Beyond the ecological interest in further studying this interaction, it may be informative about the role of population-level innate immune stimulation and/or within-host resource competition with other viruses for SARS-CoV-2 mitigation.”
Conclusion
The study exploited multiplexed PCR testing as a tool for examining pathogen-pathogen interactions and thus identifying high-risk combinations at the point of care.
With increasing ability to understand exactly the causes of infection, future vaccine development and implementation, treatments, and public health priorities could be tailored and thus reduce the extreme burden of respiratory infections affecting billions of individuals worldwide.”
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
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