Immunologic and inflammatory consequences of SARS-CoV-2 infection and its implications in renal disease

Abstract

The emergence of the COVID-19 pandemic made it critical to understand the immune and inflammatory responses to the SARS-CoV-2 virus. It became increasingly recognized that the immune response was a key mediator of illness severity and that its mechanisms needed to be better understood. Early infection of both tissue and immune cells, such as macrophages, leading to pyroptosis-mediated inflammasome production in an organ system critical for systemic oxygenation likely plays a central role in the morbidity wrought by SARS-CoV-2. Delayed transcription of Type I and Type III interferons by SARS-CoV-2 may lead to early disinhibition of viral replication. Cytokines such as interleukin-1 (IL-1), IL-6, IL-12, and tumor necrosis factor α (TNFα), some of which may be produced through mechanisms involving nuclear factor kappa B (NF-κB), likely contribute to the hyperinflammatory state in patients with severe COVID-19. Lymphopenia, more apparent among natural killer (NK) cells, CD8+ T-cells, and B-cells, can contribute to disease severity and may reflect direct cytopathic effects of SARS-CoV-2 or end-organ sequestration. Direct infection and immune activation of endothelial cells by SARS-CoV-2 may be a critical mechanism through which end-organ systems are impacted. In this context, endovascular neutrophil extracellular trap (NET) formation and microthrombi development can be seen in the lungs and other critical organs throughout the body, such as the heart, gut, and brain. The kidney may be among the most impacted extrapulmonary organ by SARS-CoV-2 infection owing to a high concentration of ACE2 and exposure to systemic SARS-CoV-2. In the kidney, acute tubular injury, early myofibroblast activation, and collapsing glomerulopathy in select populations likely account for COVID-19-related AKI and CKD development. The development of COVID-19-associated nephropathy (COVAN), in particular, may be mediated through IL-6 and signal transducer and activator of transcription 3 (STAT3) signaling, suggesting a direct connection between the COVID-19-related immune response and the development of chronic disease. Chronic manifestations of COVID-19 also include systemic conditions like Multisystem Inflammatory Syndrome in Children (MIS-C) and Adults (MIS-A) and post-acute sequelae of COVID-19 (PASC), which may reflect a spectrum of clinical presentations of persistent immune dysregulation. The lessons learned and those undergoing continued study likely have broad implications for understanding viral infections' immunologic and inflammatory consequences beyond coronaviruses.

Keywords: AKI; COVID-19; PASC; SARS-CoV-2; inflammasome; inflammation; long COVID.

Figure 1

Early immune response to SARS-CoV-2 infection. (A) SARS-CoV-2 virions are inhaled through respiratory and aerosolized droplets (–26). Infection of susceptible cell types, particularly those bearing ACE2 and TMPRSS, such as Type II pneumocytes, can occur (27, 28). (B) Viral entry can occur through mechanisms including host-membrane fusion (29). Entry is followed by the release and translation of ORF1a and ORF1b of SARS-CoV-2 ssRNA, formation of the viral replication and transcription complex (23), and production of new SARS-CoV-2 virions, which are eventually exocytosed. (C) Resident macrophages are likely among the first immune cells to encounter SARS-CoV-2 through both direct infection and indirect immune activation. As with other cells, TLR- and RLR-mediated recognition are accompanied by downstream effects through Myd88 activation, TRIF binding (43, 45, 50), MAVS activation (45), and NF-κB activation (45, 52). (D) Production of Type I and Type III interferons appears to be blunted in the early immune response (42, 89) despite their antiviral potential. (E) Infection and activation with SARS-CoV-2 may induce inflammasome production and macrophage pyroptosis, which may be a key early driver of a heightened immune response following SARS-CoV-2 infection (57). (F) One such mechanism is through cytokine and chemokine release (70, 103, 104), including TNFα, TGF-β, CCL2/3, CXCL9/10, IL-1β, IL-2, IL-6, IL-10, IL-17, IL-21, and IL-22 (see text for references). (G) The early immune response may also be mediated by pre-existing cross-reactive antibodies (–177) and plasmablast development (173). (H) Endothelial cell infection may also occur (207); endothelial cell activation may be associated with a hypercoagulable state (210, 211). (I) Early neutrophil responses include the production of immature neutrophils through emergency myelopoiesis (115, 400) and neutrophil extracellular trap (NET) formation, which may also contribute to microvascular thrombosis (111, 117). (J) Soluble pattern recognition molecules such as mannose-binding lectin (MBL) and pentraxin three can bind to SARS-CoV-2 spike and nucleocapsid proteins, respectively (96). (K) Lymphopenia, which often accompanies COVID-19 (408), can include the peripheral depletion of cell types such as Innate Lymphoid Cells (ILC) (126, 127), MAIT (127), NK-cells (124, 398), and γδ-T-cells (136).

Figure 2

Lymphocyte response in acute and post-acute SARS-COV-2. (A) Lymphopenia is a hallmark of COVID-19 (408). (B) Among the cell types present, CD4+ T-cells skew towards T_H1 and T_FH phenotypes with associated effector functions (145, 151); germinal center T_FH may be decreased (151). Upregulation of T_H17-cells can occur [in contrast to T_reg (156)] and may be accompanied by the pro-inflammatory release of IFN-γ, GM-CSF, IL-10, IL-17A, IL-17F, IL-21, and IL-22 (155). (C) CD8+ cells exhibit activated phenotypes with preserved effector function and a potential role in macrophage-mediated cytokine release in acute COVID-19 (137, 161, 163) despite showing peripheral depletion (139, 144, 159, 160). (D) B-cells are also peripherally depleted in COVID-19 (173, 181). Plasmablast development occurs at first in extrafollicular zones (173), initially with less sophisticated targeting (173, 181) via DN2 and DN3 B-cells (181), but later [at approximately seven days post-infection (181)] with more robust class-switching, somatic hypermutation and affinity maturation (173) from germinal center (GC) cells. (E) Autoantibody development, including those directed towards interferons, can develop at this time (309) and may later be associated with PASC (285). (F) In the post-acute phase, effector CD4+ T-cell subtypes may remain active for at least 2-3 months (285). Decreased levels of naïve CD4+ T-cells suggest ongoing activation (301). Memory T-cells (which can develop early in the course of infection) can include those of the CD4+ and CD8+ T-cells and subtypes (165, 406), and may be detected at least one year post-infection (165). S-specific CXCR3-/CXCR5-/CCR6+ T_H17-cells can have a half-life of 4.9 years (405). Memory T-cells may be important drivers of vaccine-mediated immunity (194, 195). (G) CD8+ T-cells may continue to exhibit markers of activation and exhaustion (PD-1 and TIM-3) at three months, particularly in patients with PASC, and have been observed to persist for up to 8 months (301). Memory CD8+ T-cells may have a half-life of one year (405); this can vary by disease severity (405). (H) Depletion of naïve B-cells suggests ongoing activation at eight months (301). Memory B-cell (MBC) frequency may correlate with decreased symptom duration (403) and may also have a role in vaccine-mediate immunity, even as antibody levels subside (192). MBC associated with autoantibody or SARS-CoV-2-directed antibody production may also be associated with varying PASC symptomatology (285). Of note, autoantibody production may occur early and may precede COVID-19 diagnosis (285).

Figure 3

Acute, post-acute and chronic end organ manifestations of SARS-CoV-2 infection. SARS-CoV-2 may have adverse clinicopathophysiological impacts on multiple organ systems throughout the body. (A) Early effects are shown here and may include delirium, stroke, cardiomyopathy, myocardial infarction, pneumonia, ARDS, and AKI. (B) Postacute and chronic end-organ manifestations of SARS-CoV-2 infection can include neuropsychiatric symptoms such as fatigue and POTS (which may be features of PASC), in addition to myocarditis, interstitial lung disease and CKD.

Figure 4

Inflammatory and immunologic consequences of SARS-CoV-2 in the kidney. (A) Histological and pathological mechanisms of acute kidney injury (AKI) in SARS-CoV-2 infection include collapsing glomerulonephritis, myoglobin cast nephropathy, proliferative glomerulonephritis with monoclonal IgG deposits, sequelae of nephrotoxic agents, acute tubular injury and necrosis (267), and perfusion pressure changes. More recent studies suggest that early tubule-interstitial fibrosis can occur in the setting of upregulated pro-fibrotic and pro-inflammatory mechanisms accompanied by myofibroblast activation, collagen, and ECM deposition. (B) Mechanisms of the development of chronic kidney disease (CKD) can include natural progression from AKI (414), which may occur as a result of maladaptive repair manifesting as early myofibroblast activation through proinflammatory pathways such as TGF-β, decreased Ang 1-7 production, and concomitant ongoing ECM and collagen deposition through mechanisms set off during the COVID-19 AKI phase. Direct damage to podocytes and proximal convoluted tubules via SARS-CoV-2 colocalization with Le^x and sialyl-Le^x (CD15s) in addition to ACE2 in the setting of chronic replication of SARS-CoV-2 may occur in immunocompromised hosts (365). Progression of pre-existing CKD may occur following COVID-19. In renal PASC, mildly decreased eGFR is likely to occur as a less clinically significant manifestation of SARS-CoV-2 infection. Additional mechanisms include CKD as a sequela of the array of etiologies of AKI in acute infection (414). Long-term sequelae of COVID-19 may also include subclinical decreased creatinine clearance (366), presumably through the mechanisms described for more overt CKD phenotypes. Persistent viral RNA may be present in immunocompetent patients and has been suggested as one mechanism for PASC (291).