Immune responses in COVID-19 patients: Insights into cytokine storms and adaptive immunity kinetics

Abstract

SARS-CoV-2 infection can trigger cytokine storm in some patients, which characterized by an excessive production of cytokines and chemical mediators. This hyperactive immune response may cause significant tissue damage and multiple organ failure (MOF). The severity of COVID-19 correlates with the intensity of cytokine storm, involving elements such as IFN, NF-κB, IL-6, HMGB1, etc. It is imperative to rapidly engage adaptive immunity to effectively control the disease progression. CD4⁺ T cells facilitate an immune response by improving B cells in the production of neutralizing antibodies and activating CD8⁺ T cells, which are instrumental in eradicating virus-infected cells. Meanwhile, antibodies from B cells can neutralize virus, obstructing further infection of host cells. In individuals who have recovered from the disease, virus-specific antibodies and memory T cells were observed, which could confer a level of protection, reducing the likelihood of re-infection or attenuating severity. This paper discussed the roles of macrophages, IFN, IL-6 and HMGB1 in cytokine release syndrome (CRS), the intricacies of adaptive immunity, and the persistence of immune memory, all of which are critical for the prevention and therapeutic strategies against COVID-19.

Keywords: Adaptive immunity; COVID-19; Cytokine storm; Immune memory; SARS-CoV-2.

Fig. 1

illustrated the pathophysiological cascade following SARS-CoV-2 invasion of lung. Virus triggers the differentiation of AM into the M1 phenotype. These M1 AM release pro-inflammatory cytokines to precipitate local inflammation. This inflammation escalates the production of pro-inflammatory cytokines and chemokines, which contribute to CRS. Concurrently, the inflammatory mediators suppress the formation of protective surfactant (PS), while the viral progeny propagated by M1 cells continue to infect type II alveolar epithelial cells (ATII), further exacerbating the condition.

Fig. 2

Upon invasion by SARS-CoV-2, pDCs express TLR-7 and TLR-9, initiating signaling through MyD88 and IRF-7 that induce type I IFN responses, resulting in the substantial secretion of IFN-α/β. Subsequently, dsRNA activates TLR-3 through the involvement of TRIF and TRAF-3, culminating in the release of NF-κB and numerous pro-inflammatory cytokines. The interaction between HMGB1 and TLR4 triggers the TLR signaling pathway through the intermediation of MyD88 and TRIF. Subsequently, this leads to the activation of NF-κB. Concurrently, the binding of HMGB1 to the RAGE initiates the Ras-mediated activation of ERK and p38, culminating in NF-κB pathway activation. This sequence of events promotes the translocation of NF-κB to the nucleus, fostering the transcription of various proinflammatory genes and synthesis of pro-IL-1β, pro-IL-18, IL-6 and TNF-α. Caspase 1 processes pro-IL-1β and pro-IL-18 into their mature forms, IL-1β and IL-18, thereby contributing to CRS associated with SARS-CoV-2 infection.

Fig. 3

illustrated that the S and N proteins of SARS-CoV-2 constitute the primary antigens for generation of specific antibodies. Upon activation of the adaptive immune response, select B cells transform into plasma cells that produce quantities of antibodies, including IgM, IgA, IgG, and neutralizing antibodies, which function to directly neutralize virus. Concurrently, another subset of B lymphocytes mature into memory cells for long-term immunity. SARS-CoV-2-specific CD4⁺ T cells predominantly secrete IFN-γ and often differentiate into T helper 1 (Th1) and T follicular helper (TFH) cells. Th1 cells promote antiviral responses through the production of IFN-γ and associated cytokines, whereas TFH cells are integral to the generation of neutralizing antibodies, the sustenance of memory B cells, and the establishment of enduring humoral immunity. Additionally, specific CD4⁺ T cells may become Th17 cells, releasing interleukin-22 (IL-22) to aid in the repair of lung tissue. SARS-CoV-2-specific CD8⁺ T cells show elevated levels of activation markers and cytotoxic molecules, playing a pivotal role in the eradication of the virus and infected host cells.

Fig. 4

illustrated the timeline of immune responses following SARS-CoV-2 infection. Typically, effector T cells and B cells proliferate in significant numbers within 6–10 days post-invasion. Subsequent to the adaptive immune system's successful eradication of the virus, an enduring immune memory is established, enduring for a variable duration. Recent studies had documented immune memory persistence for up to 2 years, marking the longest observed follow-up interval to date.