A study conducted by researchers from the Universidade Federal do ABC (UFABC) in São Paulo, Brazil, in collaboration with Cambridge University and the University of St Andrews in the UK, has shed new light on the role of the SARS-CoV-2 accessory protein, ORF8, in modulating cytokine responses and its impact on the immune system.
The severity of SARS-CoV-2 infection is often associated with an overactive immune response, leading to a cytokine storm characterized by excessive pro-inflammatory cytokine production. The study highlights the crucial role of ORF8 in this process. ORF8, a unique protein in the SARS-CoV-2 genome, shares similarities with a bat coronavirus, suggesting a potential origin from bats. It is highly susceptible to mutations, with the L84S variant being prevalent in the early months of the pandemic and associated with milder disease outcomes.
Structural analysis of ORF8 reveals its distinct characteristics, including disulfide bonds and glycosylation, which contribute to its stability and immunogenicity. Despite being classified as an accessory protein, ORF8 has the largest protein interactome network among SARS-CoV-2 accessory proteins, indicating its broad functional roles.
The study delves into the impact of ORF8 on cytokine responses, specifically its modulation of type I interferon (IFN) and interleukin-6 (IL-6). ORF8 has been found to enhance IL-6 production and may act through pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) that recognize double-stranded RNA (dsRNA). This finding highlights ORF8’s role in immune dysregulation and the cytokine storm observed in severe cases of COVID-19.
The immune response to SARS-CoV-2 involves both innate and adaptive immunity. Failure to mount an adequate adaptive response can lead to a continuous cytokine storm and multi-organ infection. SARS-CoV-2 employs various mechanisms, including ORF8, to evade the immune system and antagonize both innate and adaptive immune responses. ORF8 interacts with major histocompatibility complex class I (MHC-I), inhibiting T cell-mediated lysis of infected cells.
The study also reveals that ORF8 has diverse functions beyond immune evasion. It has been implicated as a pro-inflammatory virokine, inducing inflammatory responses by mimicking the pro-inflammatory cytokine IL-17 and activating downstream inflammatory pathways. Furthermore, recent studies suggest that ORF8 might activate TLRs, especially those recognizing dsRNA, such as TLR3, further influencing the immune response and cytokine modulation.
Understanding the multifaceted functions of ORF8 is crucial for developing targeted therapeutic strategies against COVID-19. Future research should focus on exploring the impact of ORF8 on different cell types, its role in viral evolution, and elucidating the precise signaling pathways through which it exerts its effects. Unraveling the complexities of ORF8 function will contribute to the development of more effective treatments and enhance our preparedness for future viral threats.