Virus World

Several SARS-CoV-2 proteins have been shown to counteract the host innate immune response, mostly using in vitro protein expression, which may not fully reflect their role in the context of viral infection. In addition, while each viral protein was characterized in a different experimental system, their relative contribution in immunosuppression remains unclear. Here we used a SARS-CoV-2 bacterial artificial chromosome with en passant mutagenesis to recover a panel of twelve infectious recombinant SARS-CoV-2 viruses, each with mutations in either NSP1, NSP2, NSP3, NSP6, NSP12, NSP13, NSP14, NSP15, NSP16, ORF3a, ORF6 or ORF8. We used the interferon-stimulated response element (ISRE)-driven luciferase assay in 293T-ACE2/TMPRSS2 cells to test the panel, demonstrating that mutations in many proteins, especially in NSP1 and NSP15, increased the type I interferon response relative to the parental wild-type virus.

RNA-seq analysis of mutant-virus infected Calu-3 cells showed that the mutations in NSP1 or NSP15 lead to higher expression of multiple genes involved in innate immune response, cytokine-mediated signaling and regulation of lymphocyte proliferation. Furthermore, mutations in either NSP1 or NSP15 resulted in a greater maturation of human monocyte-derived dendritic cells in vitro. Infection of K18 hACE2 transgenic mice with either NSP1 or NSP15 mutated viruses demonstrated attentuated respiratory tract replication. Analysis of lung immune cells from infected mice by single-cell RNA-seq identified 15 populations of major myeloid and lymphoid cells with changes in the pattern of their activation associated with viral infection. The effects of mutations in NSP1 or NSP15 on these responses are consistent with differences in the immunosuppressive mechanisms utilized by the two proteins. Overall, these data demonstrate different and redundant mechanisms of innate immune antagonism by SARS-CoV-2 and suppression of activation of antigen presenting cells and T and B lymphocytes mediated by multiple viral proteins.

Preprint in bioRxiv (Jan. 29, 2024):

 https://doi.org/10.1101/2024.01.29.577695 

Severe COVID-19 may cause long-lasting alterations to the innate immune system, the first line of defense against pathogens, according to a small study funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.  These changes may help explain why the disease can damage so many different organs and why some people with long COVID have high levels of inflammation throughout the body. The findings were published online today in the journal Cell. Researchers led by Steven Z. Josefowicz, Ph.D., of Weill Cornell Medicine in New York City examined immune cells and molecules in blood samples from 38 people recovering from severe COVID-19 and other severe illnesses, as well as from 19 healthy people. Notably, the researchers established a new technique for collecting, concentrating and characterizing very rare blood-forming stem cells that circulate in the blood, eliminating the need to extract such cells from bone marrow.

In these rare stem cells-;the parents of immune-system cells-;taken from people recovering from COVID-19, the scientists identified changes in the instructions for which genes got turned on or off. These changes were passed down to daughter cells, leading them to boost production of immune cells called monocytes. In the monocytes from people recovering from severe COVID-19, the changes in gene expression led the cells to pump out greater amounts of molecules called inflammatory cytokines than monocytes from people who were healthy or had non-COVID-19 illnesses. The researchers observed these changes as much as a year after the participants came down with COVID-19. Due to the small number of study participants, the scientists could not establish a direct association between the cellular and molecular changes and health outcomes. The investigators suspected that an inflammatory cytokine called IL-6 might play role in establishing the changes in gene-expression instructions. They tested their hypothesis both in mice with COVID-19-like disease and in people with COVID-19. In these experiments, some of the subjects received antibodies at the early stage of illness that prevented IL-6 from binding to cells. During recovery, these mice and people had lower levels of altered stem cell gene-expression instructions, monocyte production and inflammatory cytokine production than subjects that didn't receive the antibody. In addition, the lungs and brains of mice that received the antibodies had fewer monocyte-derived cells and less organ damage.

These findings suggest that SARS-CoV-2 can cause changes in gene expression that ultimately boost the production of inflammatory cytokines, and one type of those cytokines perpetuates the process by inducing these changes in stem cells even after the illness is over. Additionally, the findings suggest that early-acting IL-6 is likely a major driver of long-term inflammation in people with severe COVID-19. These findings shed light on the pathogenesis of SARS-CoV-2 infection and may provide new leads for therapies. The results also underscore the importance of staying up to date with recommended COVID-19 vaccines, which are proven to protect against serious illness, hospitalization and death.

Research cites published in Cell (August 18, 2023);

https://doi.org/10.1016/j.cell.2023.07.019 

Merck has struck a deal to buy OncoImmune for its COVID-19 treatment CD24Fc. The $425 million cash acquisition will give Merck control of a fusion protein linked to improvements in clinical status in a phase 3 trial of severe and critical COVID-19 patients.  OncoImmune began 2020 by presenting data on the effect of CD24Fc in allogeneic hematopoietic stem cell transplant patients. The use of CD24Fc in the population was underpinned by evidence that CD24 fusion proteins negatively regulate damage-associated molecular patterns, thereby countering a mechanism that may amplify graft-versus-host disease. As evidence of the effect of SARS-CoV-2 accrued, OncoImmune spied an opportunity to use CD24Fc to treat the sickest COVID-19 patients. OncoImmune began a clinical trial in April to test the theory that CD24Fc fortifies an innate immune checkpoint against excessive inflammation. With OncoImmune sharing interim phase 3 results to support the theory in September, Merck has agreed to pay $425 million upfront to buy the biotech. The deal is centered on CD24Fc. OncoImmune is spinning out other assets to form a new biotech owned by its existing shareholders. Merck is set to invest $50 million in the new biotech. The deal, which features undisclosed regulatory milestones and sales-based payments, adds another element to Merck’s attack on COVID-19. Merck tasked a research group to the virus in late January but was slower than some of its peers to disclose efforts to combat COVID-19. The Big Pharma made its splash in the last week of May, when it disclosed three deals for vaccines and antivirals.

Merck now has two COVID-19 vaccines in the clinic, albeit at an earlier stage than rival candidates, and an antiviral in phase 2/3 development. Those programs cover assets that may prevent infection and treat patients with mild-to-moderate COVID-19. OncoImmune moves Merck into another area of the COVID-19 response.   OncoImmune is testing CD24Fc in severe or critical COVID-19 patients. Participants in the phase 3 required supplemental oxygen support, noninvasive ventilation, high flow oxygen devices, invasive ventilation or extracorporeal membrane oxygenation. An interim review took place once 146 patients in the placebo-controlled trial experienced clinical recovery. The review linked CD24Fc to a 60% higher probability of improvement in clinical status versus placebo and a more than 50% lower risk of death or respiratory failure. The median recovery time in the CD24Fc group was six days, compared to 10 days in the control cohort.  The results suggest CD24Fc may help a population failed by multiple other drugs. The World Health Organization recommends against the use of remdesivir in hospitalized patients, anti-SARS-CoV-2 antibodies have failed in the population and efforts to repurpose existing inflammatory disease drugs floundered. Dexamethasone is a rare example of a drug that improved outcomes in severe patients.  Some patients in the OncoImmune trial received drugs including dexamethasone and remdesivir. In patients who received corticosteroids, such as dexamethasone, median time to recovery was 15 days. Median recovery time in patients who received corticosteroids and CD24Fc was five days.

An ancient conflict between hosts and pathogens has driven the innate and adaptive arms of immunity. Knowledge about this interplay can not only help us identify biological mechanisms but also reveal pathogen vulnerabilities that can be leveraged therapeutically. The humoral response to SARS-CoV-2 infection has been the focus of intense research, and the role of the innate immune system has received significantly less attention. Here, we review current knowledge of the innate immune response to SARS-CoV-2 infection and the various means SARS-CoV-2 employs to evade innate defense systems. We also consider the role of innate immunity in SARS-CoV-2 vaccines and in the phenomenon of long COVID.

Published in Cell. Mol. Immunology (Nov. 20, 2023):

https://doi.org/10.1038/s41423-023-01104-y 

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):