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 

As the flu season approaches, a strained public health system may have a surprising ally — the common cold virus.Rhinovirus, the most frequent cause of common colds, can prevent the flu virus from infecting airways by jumpstarting the body’s antiviral defenses, Yale researchers report today (September 4, 2020) in the journal The Lancet Microbe. The findings help answer a mystery surrounding the 2009 H1N1 swine flu pandemic: An expected surge in swine flu cases never materialized in Europe during the fall, a period when the common cold becomes widespread. A Yale team led by Dr. Ellen Foxman studied three years of clinical data from more than 13,000 patients seen at Yale New Haven Hospital with symptoms of respiratory infection. The researchers found that even during months when both viruses were active, if the common cold virus was present, the flu virus was not. “When we looked at the data, it became clear that very few people had both viruses at the same time,” said Foxman, assistant professor of laboratory medicine and immunobiology and senior author of the study. Foxman stressed that scientists do not know whether the annual seasonal spread of the common cold virus will have a similar impact on infection rates of those exposed to the coronavirus that causes COVID-19. “It is impossible to predict how two viruses will interact without doing the research,” she said.

To test how the rhinovirus and the influenza virus interact, Foxman’s lab created human airway tissue from stem cells that give rise to epithelial cells, which line the airways of the lung and are a chief target of respiratory viruses. They found that after the tissue had been exposed to rhinovirus, the influenza virus was unable to infect the tissue. “The antiviral defenses were already turned on before the flu virus arrived,” she said. The presence of rhinovirus triggered production of the antiviral agent interferon, which is part of the early immune system response to invasion of pathogens, Foxman said. “The effect lasted for at least five days,” she said. Foxman said her lab has begun to study whether introduction of the cold virus before infection by the COVID-19 virus offers a similar type of protection.

Published in the Lancet Microbe (Sept. 4, 2020):

https://doi.org/10.1016/S2666-5247(20)30114-2

Just two days after announcing its R&D chief was stepping down, Gilead Sciences has announced it will be buying up a few of Novartis’ unwanted early-stage infection assets. The West Coast Big Biotech, which has been shuffling its execs over the past few weeks, today licensed three preclinical antiviral programs from Novartis including investigational agents with the potential to treat human rhinovirus, influenza and herpes.

For its part, Novartis gets an undisclosed upfront payment, with biobucks worth $291 million as well as royalties on annual net sales. “Today’s announcement builds on Gilead’s heritage in antiviral research and development. We look forward to applying this expertise to advance the development of potential new treatments for viruses with limited therapeutic options,” said John McHutchison, M.D., Gilead’s outgoing chief scientific officer and head of R&D. 

Gilead has been pivoting toward cancer in recent years, most notably though its $12 billion buyout of Kite Pharma and its CAR-T drugs, but anti-infectives against hepatitis C and HIV remain the base of the company and seemingly still an important part of its future.

Can prior exposure to other respiratory viruses like the common cold before infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen responsible for the coronavirus disease 2019 (COVID-19), offer protection against COVID-19?  Researchers at the Yale School of Medicine found that rhinovirus, which is the virus that is most commonly responsible for the common cold, accelerates interferon-stimulated genes (ISG), which are early response molecules in the immune system. The increased expression of these genes was found to prevent SARS-CoV-2 replication within airway tissues that were previously infected with rhinovirus. The study, which was published in the Journal of Experimental Medicine, shed light on the use of interferons (IFNs), which are immune system proteins, in COVID-19 patients. The researchers also noted that IFN treatment could be used for prophylactic purposes in high-risk patients who have been exposed to SARS-CoV-2.

The study

The initial replication of SARS-CoV-2 in the upper respiratory tract is needed to establish infection. In SARS-CoV-2 infection, the virus enters lung cells through the angiotensin-converting enzyme 2 (ACE2) receptor. The cell-free and macrophage-phagocytosed virus can then spread to other organs and infect ACE2-expressing cells at local sites, which can cause multi-organ injury. Previous studies demonstrated that at the later stages of COVID-19, high IFN levels coincide with a more severe disease that is likely due to a hyperactive immune response. However, recent evidence has demonstrated that ISG instead offers protection during SARS-CoV-2 infection. This work was largely inspired by previous studies that found that common cold viruses may offer protection against the influenza virus. The researchers aimed to determine whether rhinoviruses would provide a similar beneficial effect against SARS-CoV-2.

Study findings

First, the team sought to capture early host-virus dynamics in the human nasopharynx using serial patient samples. Through the use of transcriptomics and biomarker-based tracking in these samples, the researchers observed a robust induction of ISG in the airway mucosa of these COVID-19 patients. Furthermore, ISG levels were found to align with viral load levels in these patients, with patients with the highest viral load tending to have higher ISG expression levels than those with the lowest viral loads. The researchers also studied the functional consequences of modulating the host innate immune response in primary human airway epithelial air-liquid interface organoid cultures. When the researchers infected lab-grown human airway tissue with SARS-CoV-2, they found that the viral load in the tissue doubled every six hours for the first three days. Meanwhile, the replication of SARS-CoV-2 was halted entirely in the tissue that was previously exposed to rhinovirus. When the antiviral defenses were blocked, SARS-CoV-2 successfully replicated in the tissues previously exposed to the common cold virus. The results showed that SARS-CoV-2 induces an IFN response in the nasopharynx across diverse patient groups. The same protective defenses were found to slow infection with SARS-CoV-2 even without prior exposure to rhinovirus.

Study takeaways

Taken together, the current study found that the defenses mediated by ISG at the time of SARS-CoV-2 exposure play an important role in determining infection severity. The heterologous antiviral response that is triggered by a different virus can therefore offer protection against SARS-CoV-2. The study findings also explain the phenomenon that occurs when common colds are frequent at certain times of the year, during which the rates of infections with other viruses like influenza tend to decrease. However, the researchers fear that such respiratory viruses can become stronger as a result of their dormancy over the past year due to social distancing measures. When these restrictions are eased, cases of common colds and other viral infections may arise. IFN treatment now holds promise as a preventive treatment for COVID-19. The researchers warned that the efficacy of this treatment approach will likely depend on the timing of its use. Based on theories, IFN treatment could be used as a prophylactic measure in high-risk patients. Currently, IFN treatments are being investigated in clinical trials, which have shown their beneficial use if given early in the course of the infection. In addition to vaccination efforts, finding a potential preventive measure for COVID-19 remains crucial as the world continues to grapple with this disease.

Original findings published in the Journal of Exp. Medicine (June 15, 2021):

Defending against viruses is one of the thorniest problems in medicine. Vaccines have been a major success story but can still only fend off a fraction of known viruses. They work by “teaching” our immune system to recognize a specific virus so it can mount an effective immune response if it spots that invader in future. Another approach is the use of antivirals, which prevent viruses from replicating and can be used to treat a current infection if administered quickly. Developing safe antivirals is difficult, however, because viruses hijack the host’s own cellular machinery in order to replicate, so interfering can also harm host cells.

A problem for both approaches is the huge diversity of viral pathogens. For instance, the viral group responsible for at least half of all cases of the common cold—rhinovirus–has at least 160 different types. Developing more than 100 vaccines to cure one illness is obviously not practical, and in any case, other viruses also cause colds. Complicating matters further, many viruses can mutate in ways that make them resistant to drugs or capable of overcoming immunity. All of which is why an important goal in virology is the development of “broad spectrum” antivirals that are effective against many viruses simultaneously.

In a study published Monday in Nature Microbiology, microbiologist Jan Carette of Stanford University and his colleagues report they have found a human gene that produces a protein essential to the function of numerous enteroviruses, a genus that includes rhinoviruses. Experiments in human cells and mice showed a range of enteroviruses cannot replicate without this host protein. The work could pave the way for antivirals effective against multiple illnesses—including most cases of the common cold—and sheds new light on how viruses exploit their host’s own cellular material.  Carette and his colleagues have “done a tour de force here, to find this gene and characterize it,” says Ann Palmenberg, a virologist at the University of Wisconsin-Madison, who provided some advice and materials for the study but was not directly involved in it. “It’s a beautiful piece of work.”

Enteroviruses also include poliovirus, coxsackievirus (which causes myocarditis, or heart inflammation) and EV-D68, a virus that has been linked to acute flaccid myelitis . To search for commonalities between these viruses, the researchers used cutting-edge gene-editing technology to inactivate single genes from human cells grown in a lab dish. First they created a bank of cells that each lacked a different gene, spanning the whole human genome. Then they infected these cells with two enteroviruses: EV-D68 and a “type-C” rhinovirus called RV-C15. The latter is a fairly newly discovered rhinovirus type that can seriously exacerbate asthma symptoms and increase the risk of infected infants developing asthma and chronic obstructive pulmonary disease. Although they are both enteroviruses, EV-D68 and RV-C15 are relatively distant relations that mostly make use of different host-cell proteins. The team then looked at which genes were missing in cells that continued to flourish after infection, focusing on the few whose absence thwarted both viruses. In addition to two genes that produce proteins known to be needed by enteroviruses, one little known one stood out: SETD3, which makes a protein of the same name. Carette and his colleagues next investigated how widely enteroviruses, in general, depend on the protein SETD3. They created cells lacking SETD3 and infected them with seven viruses representative of the different species of human enteroviruses: one of each of the three types of rhinovirus (A, B and C), poliovirus, two types of Coxsackievirus and EV-D68. None of these could flourish in SETD3-deficient cells—their replication rate was reduced 1,000-fold as compared with control cells that possessed the gene....

Original findings published on September 16, 2019 in Nature Microbiology:

https://doi.org/10.1038/s41564-019-0551-1