A study conducted at Johns Hopkins University School of Medicine in Baltimore has revealed distinct differences in the immune pathways that are activated by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and those that are activated by influenza.
The development could lead to potential therapeutic approaches to coronavirus disease 2019 (COVID-19) – the illness caused by SARS-COV-2.
Studies have called into question the uniqueness of the inflammatory profile observed in cases of COVID-19.
Influenza is also a virus that causes severe pneumonia, and it is not yet clear how immune pathways in SARS-CoV-2 infection cause more severe disease than other viruses, says Andrea Cox and colleagues.
However, the researchers have now shown that although SARS-CoV-2 and influenza are both respiratory viruses, they induce distinct inflammatory pathways.
“These findings point to activation of fundamentally different innate immune pathways in SARS-CoV-2 and influenza infection, and emphasize drivers of severe COVID-19 to focus both mechanistic and therapeutic investigations,” writes Andrea Cox and the team.
A pre-print version of the research paper is available on the medRxiv* server, while the article undergoes peer review.
Cytokine upregulation in SARS-CoV-2 infection
Since the SARS-CoV-2 virus was first identified in Wuhan, China, in late 2019, its unprecedented spread has led to more than 103 million infections and more than 2.25 million deaths globally.
The disease course in COVID-19 is highly variable, ranging from asymptomatic to severe disease that causes multi-organ damage and death.
One feature of severe disease is immune dysregulation characterized by raised levels of pro-inflammatory markers and inflammatory cytokines, including interleukin (IL)-6, IL-10, IP-10, and IL-1RA.
Clinical trials of targeted anti-inflammatory therapies such as IL-6 and IL-1 antagonists have shown that these agents have a modest beneficial effect.
“However, studies have called into question the uniqueness of the inflammatory cytokine profile of COVID-19 by highlighting similarities to sepsis or acute respiratory distress syndrome (ARDS) due to other causes,” writes Cox and colleagues.
For example, many of the cytokines that are elevated in severe COVID-19 are also elevated in influenza.
“Thus, it is unclear what is unique to cytokine upregulation in SARS-CoV-2 infection that leads to more severe disease than with other viruses,” says the team.
Investigating how BMI may alter immune pathways
One known risk factor for severe COVID-19 is an elevated BMI, with obese individuals at an increased risk for hospitalization and death.
Many studies have reported an association between elevated BMI and increases in IL-10, IL-6, and IL-1RA. Yet, few analyses of inflammatory cytokines in studies of COVID-19 have taken this variable into account, says Cox and colleagues.
What did the researchers do?
The researchers measured 37 cytokines in patients hospitalized with either COVID-19 (n=145) or influenza (n=57) and measured the association between levels of these inflammatory mediators and disease severity. Thirty health individuals were included as a control group.
The team also conducted a mediation analysis to determine whether certain cytokines mediate BMI's effect on disease severity.
Linear regression analysis was used to determine BMI, age, and sex, differences in cytokines between the different groups and random forest prediction was used to identify the most important cytokines for distinguishing between severe COVID-19 and severe influenza.
What did they find?
Among the severe COVID-patients, the team observed increased levels of cytokines associated with a pro-inflammatory macrophage phenotype, including IL-18, IL-6, and tumor necrosis factor-alpha (TNF-α).
Among patients with severe influenza on the other hand, increases in levels of cytokines associated with T cell activation such as IL-15 and IFN-γ were observed.
The researchers say that while treatment with steroids has proved beneficial in the late stages of COVID-19, it is not beneficial at the early stage of disease.
“Given the association with severe COVID-19 and a pro-inflammatory macrophage phenotype, targeting of the cytokines mediating MAS [macrophage activation syndrome], singly or in combination, might provide a more specific approach to immune modulation,” they suggest.
An elevated IL-6 level and a low IFN-λ1 level were identified as the most distinct features of severe COVID-19, compared with severe influenza.
However, the researchers do not yet know whether these cytokine disparities mediate the pathology differences or merely correlate other distinct immune responses.
What about BMI?
Finally, the researchers identified IL-1RA as a potential mediator of the effect of BMI on COVID-19 severity.
Adipocytes (fat-storing cells) are a major source of IL-1RA and a higher BMI provides more adipose tissue to produce this acute phase reactant, says the team. This could help to explain the underlying relationship between obesity and severe COVID-19.
“This was an unexpected finding given the anti-inflammatory nature of this cytokine,” writes Cox and colleagues. “The role of IL-1RA in pathogenesis warrants additional investigation.”
Overall, the researchers say that the comparison of cytokines elevated in COVID-19 and in influenza has revealed that disparate immune pathways are activated in these potentially life-threatening respiratory viral infections.
“In summary, this study demonstrates activation of a pro-inflammatory cytokine macrophage pathway and a role for IL-1RA in severe COVID-19, highlighting potential therapeutic targets,” they conclude.
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.