Virus World

All respiratory viruses establish primary infections in the nasal epithelium, where efficient innate immune induction may prevent dissemination to the lower airway and thus minimize pathogenesis. Human coronaviruses (HCoVs) cause a range of pathologies, but the host and viral determinants of disease during common cold versus lethal HCoV infections are poorly understood. We model the initial site of infection using primary nasal epithelial cells cultured at air-liquid interface (ALI).

HCoV-229E, HCoV-NL63 and human rhinovirus-16 are common cold-associated viruses that exhibit unique features in this model: early induction of antiviral interferon (IFN) signaling, IFN-mediated viral clearance, and preferential replication at nasal airway temperature (33°C) which confers muted host IFN responses. In contrast, lethal SARS-CoV-2 and MERS-CoV encode antagonist proteins that prevent IFN-mediated clearance in nasal cultures. Our study identifies features shared among common cold-associated viruses, highlighting nasal innate immune responses as predictive of infection outcomes and nasally-directed IFNs as potential therapeutics.

Preprint in bioRxiv (Dec.19, 2023):

https://doi.org/10.1101/2023.12.18.571720 

Over a few weeks in November 1889, a respiratory disease attacked half the residents of St. Petersburg, Russia, and it soon began to race through Europe and the rest of the world. Two years later, in a spectacularly detailed book, a British medical officer, H. Franklin Parsons, described what was dubbed the “Russian influenza” epidemic, which raged until 1894. People seemed to spread the disease before developing symptoms, the young did not suffer as much as the old, a dry cough was common among the ill, some had a “perversion of taste and smell,” and deaths rose. Suspicions ran high that a pathogen had jumped from an animal into humans. Sound like COVID-19?

In 2005, scientists in Belgium proposed that the earlier pandemic’s cause was not an influenza virus, but rather a coronavirus. Three years before their theory was published, a coronavirus had passed from an animal to humans, touching off a highly lethal outbreak of what was called severe acute respiratory syndrome (SARS). The disease spread from China and brought new attention to these once-obscure viruses. The Belgian team wondered whether something similar happened in Russia more than a century ago. Based on molecular clues, they suggested that the once-deadly virus is still circulating today, as a coronavirus known as OC43 that in most people causes nothing worse than a cold. So far there’s no direct evidence to back the group’s theory, but two other teams soon hope to look at tissue samples from the late 19th century to see whether they can spot when the virus first became a human pathogen.

This upcoming search for OC43’s roots is part of a flurry of research, since COVID-19 erupted globally 4 years ago this month, on it and the three other coronaviruses that cause common colds. Long ignored except by a tiny scientific community, these pathogens with clunky, alphanumeric names—NL63, 229E, and HKU1 are the other three—are now getting their due. Some groups are reexamining how the viruses leapt from animals to people, in part to understand how SARS-CoV-2, COVID-19’s cause, may have emerged. Studying the four may also illuminate whether other coronaviruses discovered in wild and domesticated animals pose a threat to humanity. And some scientists are exploring how immune responses to these four overlap and interact with the response to SARS-CoV-2...

In the current COVID-19 pandemic a key unsolved question is the duration of acquired immunity in recovered individuals. The recent emergence of SARS-CoV-2 precludes a direct study on this virus, but the four seasonal human coronaviruses may reveal common characteristics applicable to all human coronaviruses.

We monitored healthy subjects over a time span of 35 years (1985-2020), providing a total of 2473 follow up person-months, and determined a) the time to reinfection by the same seasonal coronavirus and b) the dynamics of coronavirus antibody depletion post-infection. An alarmingly short duration of protective immunity to coronaviruses was found. Reinfections occurred frequently at 12 months post-infection and there was for each virus a substantial reduction in antibody levels as soon as 6 months post-infection.

Preprint Available (June 16, 2020):

https://doi.org/10.1101/2020.05.11.20086439

Article published in Nat. Medecine (Sept. 14, 2020):

https://doi.org/10.1038/s41591-020-1083-1

SARS-CoV-2-reactive T cells are detected in some healthy unexposed individuals. Human studies indicate these T cells could be elicited by the common cold coronavirus OC43. To directly test this assumption and define the role of OC43-elicited T cells that are cross-reactive with SARS-CoV-2, we develop a model of sequential infections with OC43 followed by SARS-CoV-2 in HLA-B*0702 and HLA-DRB1*0101 Ifnar1−/− transgenic mice. We find that OC43 infection can elicit polyfunctional CD8+ and CD4+ effector T cells that cross-react with SARS-CoV-2 peptides. Furthermore, pre-exposure to OC43 reduces subsequent SARS-CoV-2 infection and disease in the lung for a short-term in HLA-DRB1*0101 Ifnar1−/− transgenic mice, and a longer-term in HLA-B*0702 Ifnar1−/− transgenic mice. Depletion of CD4+ T cells in HLA-DRB1*0101 Ifnar1−/− transgenic mice with prior OC43 exposure results in increased viral burden in the lung but no change in virus-induced lung damage following infection with SARS-CoV-2 (versus CD4+ T cell-sufficient mice), demonstrating that the OC43-elicited SARS-CoV-2 cross-reactive T cell-mediated cross-protection against SARS-CoV-2 is partially dependent on CD4+ T cells. These findings contribute to our understanding of the origin of pre-existing SARS-CoV-2-reactive T cells and their effects on SARS-CoV-2 clinical outcomes, and also carry implications for development of broadly protective betacoronavirus vaccines. The origin of SARS-CoV-2 cross-reactive T cells in unexposed humans is unclear. Here, the authors use HLA transgenic mouse models of sequential infections with human coronavirus OC43 and SARSCoV-2 and show that OC43 elicits cross-protective immunity against SARS-CoV-2, which partially depends on CD4 + T cells.

Published in Nature Communications (Jan. 26, 2024):

https://doi.org/10.1038/s41467-024-45043-2 

The COVID-19 pandemic has claimed the lives of more than one million people worldwide. The causative agent, SARS-CoV-2, is a member of the Coronaviridae family, which are viruses that cause respiratory infections of varying severity. The cellular host factors and pathways co-opted by SARS-CoV-2 and other coronaviruses in the execution of their life cycles remain ill-defined. To develop an extensive compendium of host factors required for infection by SARS-CoV-2 and three seasonal coronaviruses (HCoV-OC43, HCoV-NL63, and HCoV-229E), we performed parallel genome-scale CRISPR knockout screens.

These screens uncovered multiple host factors and pathways with pan-coronavirus and virus-specific functional roles, including major dependency on glycosaminoglycan biosynthesis, SREBP signaling, and glycosylphosphatidylinositol biosynthesis, as well as an unexpected requirement for several poorly characterized proteins. We identified an absolute requirement for the VTT-domain containing protein TMEM41B for infection by SARS-CoV-2 and all other coronaviruses. This human Coronaviridae host factor compendium represents a rich resource to develop new therapeutic strategies for acute COVID-19 and potential future coronavirus spillover events.

Preprint available in bioRxiv (October 8, 2020):

https://doi.org/10.1101/2020.10.07.326462

An analysis of four different coronaviruses over an 8-year period demonstrated that they were detected in a limited timeframe, from December to April and May, with a peak during January and February, according to a recent study published in Journal of Infectious Diseases. “This is part of a continuing study in families first designed to examine how the influenza vaccine is working in the community,” Arnold S. Monto, MD, Thomas Francis, Jr. Collegiate Professor of Public Health at the University of Michigan School of Public Health, told Healio. “We have expanded it to look broadly at all respiratory viruses.”

The four coronaviruses in the study are known to cause respiratory infections every year, according to Monto: “We had these data ready to go when the pandemic started.” Acute respiratory infections have been identified in children and adults aged 8 years and older as part of the Household Influenza Vaccine Evaluation study. Researchers obtained specimens from 890 to 1,441 individuals in Michigan, who they followed and contacted weekly in order to obtain information about acute respiratory infections. Specimens were tested for four coronavirus types: OC43, 229E, HKU1 and NL63.

Over the 8-year study period, 993 coronavirus infections were detected. The most common type was OC43 and 229E was the least common. The study showed that the coronaviruses were identified during a limited time period, from December to April/May, with a peak recorded in January or February. The viruses began to diminish in March.

Study Published in J. Infect. Diseases (April 4, 2020):

 https://doi.org/10.1093/infdis/jiaa161