Role of interferon type I-driven responses associated with disease control in COVID-19

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused over 260 million cases of coronavirus disease 2019 (COVID-19) along with five million deaths. It has affected different parts of the world differently. A new paper from Pakistan, which appeared in the journal Scientific Reports, examines the utility of type I interferon responses in predicting the clinical outcome in COVID-19.

Study: Upregulated type I interferon responses in asymptomatic COVID-19 infection are associated with improved clinical outcome. Image Credit: totojang1977/ShutterstockStudy: Upregulated type I interferon responses in asymptomatic COVID-19 infection are associated with improved clinical outcome. Image Credit: totojang1977/Shutterstock

Background

The ability to predict a protective immune response to the virus in this pandemic could help triage patients who needed differing therapeutic approaches. In Pakistan, which has seen repeated waves of infection, the case count crossed 1.28 million, with 28,000 deaths as of November 2021, though this is bound to be a significant undercount due to poor test capacity. Up to 20-40% of people at the community level are estimated to be infected, from seroprevalence studies in Karachi.

While obesity, immune deficiency, diabetes, cardiovascular disease, and renal disease are among the risk factors for severe COVID-19, in addition to male sex and advanced age, other factors that could help improve the prediction of disease severity are being sought.

The spike protein plays a key role in the infectivity of the virus, attaching to the host cell via the angiotensin-converting enzyme 2 (ACE2) receptor through its receptor-binding domain (RBD). This causes acute inflammation of the infected lung cells, with a spreading observable cytopathic effect. This leads to a cytokine storm, with the host’s innate immune response being damped while inflammasome activation occurs.

The end result is impaired adaptive immunity, with dysregulated T helper and T regulatory cells, along with elevated interleukins (IL)-4 and IL-10, inflammatory mediators that are characteristic of a Th2-type response. IL-10 impairs antiviral T cell responses.

A typical antiviral response involves both innate and adaptive immunity, the first mediated by natural killer (NK) cells, B cells and monocytes. The former is regulated by T cells, cytokines, and chemokines that attract other white cells to the site of infection. Type I Interferon (IFN) secretion drives the expression of interferon-stimulated genes (ISGs), which are associated with rapid viral clearance.

Unlike the early SARS-producing CoVs, SARS-CoV-2 seems to evade both type I and type III IFN  signaling pathways and thus successfully establishes productive infection in the target host cells. The role of type I IFN remains to be elucidated, and this was the focus of the current paper.

The scientists used RNA (ribonucleic acid) microarrays to examine the transcription products of host cells after SARS-CoV-2 infection, in asymptomatic vs symptomatic individuals with a spectrum of disease severity, as well as healthy controls.

What did the study show?

Interestingly, the transcription profile classified symptomatic patients into a different group compared to asymptomatic and control participants. Even though severely ill patients in the symptomatic group were older than the mildly or moderately ill patients, they clustered together. The most obvious differences in gene expression (differentially expressed genes, DEGs) were between the controls and symptomatic patients, though these were also seen between asymptomatic and symptomatic patients.

The genes that were most markedly activated in the symptomatic patients were CXCL8, the nuclear factor kappa beta (NF-kB) pathway, and several ribosomal proteins involved in viral infections.

Conversely, symptomatic SARS-CoV-2 patients showed suppression of genes implicated in antigen processing and presentation. Genes that are typically upregulated in infectious disease were also activated, pointing to the ability of SARS-CoV-2 to elicit both innate and adaptive immunity. This included TNFα, NFkβ, IL1, HIF1A, ICAM, and SOCS3 expression.

Conversely, in asymptomatic cases, immune regulatory genes and IFN pathway genes were expressed at elevated levels, including IFN I, II, III and alpha/beta, JAK/STAT pathway, IL-1 mediated Myd88 pathway, RIG-1 like receptor pathway, and MAPK/ERK signaling pathways.

Correspondingly, inflammatory cytokines like IL-6, TNFα, IL-1β, IL-10 and IL-21 were systemically elevated, while ILR1α, IL-1α, IL-18, VEGF and AREG levels were reduced. Since IL-18 is associated with acute respiratory distress syndrome (ARDS) following respiratory viral infection, and IL-6 with the need for mechanical ventilation, while VEGF and AREG are markers of endothelial dysfunction and pulmonary fibrosis/poor cytotoxic NK cell function, this pattern shows improved viral clearance in asymptomatic COVID-19 patients.

The findings also showed 20 ISGs to be highly expressed and eight downregulated, while several cytokine pathways were upregulated in asymptomatic COVID-19 vs. moderate or severe cases.

In severe vs mild disease, certain genes were highly expressed – one from the superfamily of Ly-6 genes, linked to neutrophil proliferation; the inflammation regulatory gene MAPKAPK2 (MAP kinase-activated protein kinase 2); the IRF2BP2 (interferon regulatory factor-2 binding protein-2) involved in suppressing the IFN response; and CXCL16 (a chemokine that attracts CXCR6-expressing activated CD8 T cells, NKT cells, and Th1-polarized T cells).

Many ISGs were markedly reduced in their level of expression. These included FIT, IFIT3, OAS1, OAS3, LY6E, and MX1.

This pattern showed that in severe COVID-19 the antibody, complement, and innate immune responses were all activated, but ribosomal protein synthesis was inhibited, along with the cytotoxicity linked to NK and T cells, as well as T cell activation and differentiation. The so-called cytokine storm has been found in progressive or severe COVID-19, and predicts a poor or fatal outcome.

What are the implications?

The researchers concluded that there were clear differences in the immune response to SARS-CoV-2 in asymptomatic COVID-19 vs symptomatic cases. In the former, innate immunity was activated by higher antigen presentation, but inflammatory and viral protein synthesis pathways were downregulated.

ISGs were upregulated in this group, along with genes regulating the antibody response. Some type I IFN responses were upregulated while others were reduced, compared to symptomatic cases.

With increasing severity of disease, more ISGs were found to be dysregulated. In severe disease, markers of neutrophil activation were elevated but ISG expression was reduced. The continued expression of inflammatory cytokines like IL-6, G-CSF, IL-1RA, and MCP1 has been found to promote a persistent entry of neutrophils into the infected tissue, causing tissue damage and the cytokine storm that reflects systemic inflammation. This is caused by elevated Th1, Th2, and Th17 responses with high circulating cytokine levels.

The increased expression of DEGs related to protein synthesis in symptomatic cases agrees with the increased synthesis of viral proteins in productive infection. At the level of adaptive T cell effector responses, the reduced antigen processing in the symptomatic group corroborates the impaired adaptive immunity reported by earlier researchers.

These findings relate to earlier variants of the virus, before the currently circulating variants of concern emerged, but show the differential activation of ISGs, IFN pathways and cytokine genes with disease severity. Asymptomatic patients showed type I IFN antiviral responses that cleared the virus from the host. Conversely, antiviral ISGs were suppressed in severe disease, allowing the virus to evade immune recognition and promoting viral replication and translation. Moreover, the downstream activation of the host immune response by the JAK/STAT pathways were also inhibited.

These data suggest that initial early responses against SARS-CoV-2 may be effectively controlled by ISGs. Therefore, we hypothesize that treatment with type I interferons in the early stage of COVID-19 may limit disease progression by limiting SARS-CoV-2 in the host.”

Journal reference:

Masood, K. I. et al. 2021. Upregulated Type I Interferon Responses in Asymptomatic COVID-19 Infection Are Associated with Improved Clinical Outcome. Scientific Reports. doi: https://doi.org/10.1038/s41598-021-02489-4. https://www.nature.com/articles/s41598-021-02489-4

Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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