The cytokine storm—An appropriate, over‐reactive response to SARS‐CoV‐2 or the wrong immune pathway?

Cytokines are proteins produced by cells of the immune system. Unusually high levels can trigger systemic pathological inflammation, referred to as a cytokine storm. The inference is that this results from a correct but over‐reactive immune response. Pathological changes consistent with cytokine storms have been observed with SARS‐CoV‐2–induced COVID‐19 disease, particularly in hospitalized patients with the severe forms of the disease. Therefore, it has been proposed that, while the virus makes people sick, what puts them in the hospital—and potentially kills them, is not the virus itself, but rather an over‐reactive immune response to the virus. ¹ , ²

In our view, the problem is not an appropriate, yet overzealous immune response. Instead, we propose that the virus incites a ‘wrong’ immune response while simultaneously suppressing a more appropriate one. Furthermore, these distinct 'appropriate' and 'incorrect' responses tilt immune balance in opposite directions.

An important survival strategy is to subvert immune attack. Specifically, it would be advantageous for the virus to suppress the most relevant T helper pathways. A large body of evidence indicates that the T helper 1 (Th1) and Th2 pathways are especially vital to clear most viral infections. Th2‐mediated robust antibody and Th1‐mediated cytotoxic T cell responses are needed to bind and neutralize the millions of viral particles produced during the acute phase of infection and to destroy infected cells used by the virus to produce myriad copies of itself. SARS‐CoV‐2 ³ and other related viruses ⁴ appear to do so by antagonizing the production and signalling of type 1 interferons (T1IFNs), which are essential initiators and amplifiers of Th1 immune responses. ⁵

Recent analyses indicate bats as the primary reservoir for the SARS‐CoV‐2 lineage and pangolins may have been an intermediate host to facilitate transmission to humans. However, it is at least as likely that the virus evolved in bats the ability to replicate in humans, perhaps decades ago. ⁶

T1IFNs are not only critical to drive Th1 cytotoxic T cell pathways, but they also play an important role in attenuating Th17 pathways, which are responsible for the recruitment of phagocytic cells. Indeed, pathways leading to Th1 and Th17 responses are mutually antagonistic. So, by targeting the T1IFN pathway, SARS‐CoV‐2 negates patients’ capacity to mount an effective Th1 response, while simultaneously enhancing a Th17 response. This scenario would predict that if a cytokine storm developed in an acutely ill patient, it would favour activation of the Th17 pathway, that which is far less likely to aid in clearing the virus. Not surprisingly that is what is found. SARS‐CoV‐2–associated cytokine storms usually consist of an overabundance of cytokines such as IL‐6, ⁷ , ⁸ which is highly associated with the Th17 pathway.

Mechanistically, the bias towards Th17 would be driven by two independent responses. The first is by altering production of interleukin‐12 (IL‐12) but not interleukin‐23 (IL‐23), which, respectively, are key drivers of Th1 and Th17 responses. T1IFNs are critical for the induction of IL‐12, ⁵ , ⁹ and they also inhibit conversion of interleukin‐1 (IL‐1) into IL‐1β, another key cytokine in the Th17 pathway. ⁵ In this circumstance, since T1IFNs suppress Th17–associated IL‐1 conversion to its active form, the immune system would tilt towards a vigorous Th17 and against a Th1 response.

Interference with IL‐12 may also contribute to the loss of Bcl‐6–expressing T follicular helper cells leading to the absence of germinal centres in some COVID‐19 patients. ⁹ , ¹⁰ This absence impairs antibody production and potentially negates B cell memory responses. Thus, the consequence of targeting T1IFN production is that the virus incites a not‐so‐helpful Th17 response and avoids the highly relevant Th1 and Th2 responses.

So, if the cytokine storm is not solely a matter of immune over‐responsiveness but rather one where the immune response is ‘barking up the wrong tree’ (in this case the Th17 rather than the Th1 tree), therapies that attenuate Th17 responses and possibly enhance Th1 responses might prevent or mitigate the cytokine storm syndrome. This could be accomplished by targeting the IL‐6 pathway and/or by using T1IFNs themselves (specifically INF‐β). Several monoclonal antibodies targeting IL‐6 and its receptors are currently in clinical trials for COVID‐19 patients, as are INF‐βs.

A corollary to this discussion is that focusing the immune response towards the Th1 pathway should lead to better outcomes, whereas amplifying the Th17 pathway would be a negative prognostic indicator of outcome. This could contribute to the greater susceptibility in older people infected with SARS‐CoV‐2, as this population has a greater tendency to polarize their immune response towards the Th17 pathway. A Th17 vs Th1 bias, however, could also explain the heterogeneous susceptibility of younger patients, and even children, to develop severe disease in the face of SARS‐CoV‐2 infection. Conversely, a Th1 bias might identify those patients most amenable to successful outcomes with targeted immunosuppressive approaches. These concepts are already in practice in the field of autoimmunity where there are strong associations between Th17‐biased immune responses and various autoimmune conditions, and where Th17 antagonists have transformed the outcomes for these patients.

In summary, we propose that the cytokine storm observed with COVID‐19 and severe symptomatology is incited by a Th17‐biased immune response, which just so happens to be a less productive pathway to clear the virus. The short‐term survival of SARS‐CoV‐2 would be favoured if the virus could force the immune system towards this incorrect response by inhibiting T1IFN pathways and thwarting the ‘correct’ and relevant Th1 pathway. Therefore, what is being referred to as a cytokine storm may really be more of a cytokine diversion. While this may seem like splitting hairs, it has important implications for therapy. It follows that therapies should not throw out the baby (Th1) with the bathwater (Th17).

CONFLICT OF INTEREST

The authors declare no conflict of interests.

AUTHOR CONTRIBUTIONS

Both authors contributed equally to writing this letter to the editor, including but not limited to conception, analysis, interpretation and design. They approved the final version.

DATA AVAILABILITY STATEMENT

Data sharing not applicable as no new data are generated.