T Cell Response to SARS-CoV-2 Coinfection and Comorbidities

Abstract

For the past three years, COVID-19 has become an increasing global health issue. Adaptive immune cells, especially T cells, have been extensively investigated in regard to SARS-CoV-2 infection. However, human health and T cell responses are also impacted by many other pathogens and chronic diseases. We have summarized T cell performance during SARS-CoV-2 coinfection with other viruses, bacteria, and parasites. Furthermore, we distinguished if those altered T cell statuses under coinfection would affect their clinical outcomes, such as symptom severity and hospitalization demand. T cell alteration in diabetes, asthma, and hypertension patients with SARS-CoV-2 infection was also investigated in our study. We have summarized whether changes in T cell response influence the clinical outcome during comorbidities.

Keywords: SARS-CoV-2; T cells; coinfection; comorbidities.

Figure 1

SARS-CoV-2 infection and T cell response. SARS-CoV-2 infects the respiratory tract by binding to the ACE2 surface receptor. Following entry via membrane fusion, it releases its viral genome in the cytoplasm. Using the host cell machinery, viral genome replication, and subgenomic transcription generate essential components needed for the virus to pack together. After the maturation of the virion, it is released from the host cell through exocytosis. When the viruses are captured and processed by antigen-presenting cells (APC), the T cells, either CD4⁺ or CD8⁺, are activated and secrete cytokines (IFNγ, TNFα, Granzyme B) to defend against viruses.

Figure 2

Changes in surface markers and cytokines following SARS-CoV-2 infection. Increased expression of surface markers including PD-1, Ki-67, HLA-DR, CD45RO, CD38hi, and CD127 was found on CD8⁺ T cells, while CD27 shows a contradicting result. Upregulation of LAG-3, TIGIT, HLA-DR, and CD45RO as well as downregulation of CD28 were detected on CD4⁺ T cells. Included in CD4 T cell subsets are Th1, Th2, Th17, Tfh, and Treg cells. Increased populations of Th1 cells along with the production of IFNγ predominated following SARS-CoV-2 infection. Conversely, low numbers of Th2 cells along with abnormal secretions of associated cytokines were found in mild patients. As for Tfh cells, lower expressions of CXCR5 and CCR6 and higher expression of ICOS were observed, while PD-1 expression had conflicting results. There were contradicting studies for Treg cells with some suggesting that high populations of Treg cells were associated with increased secretion of IL-10, TGF-β, IL-6, and IL-18. On the other hand, some researchers indicated a reduction in Treg cells, with lower expression of FOXP3, TGF-β, and IL-10. Lastly, an increased percentage of Th17 cells with high expression levels of RORγt and increased secretion of signature cytokines are found post-SARS-CoV-2 infection.

Figure 3

Role of T cells during coinfection with viruses, bacteria, and parasites. In SARS-CoV-2 coinfection with HBV, exhausted T cells are caused by HBV infection and subsequently countered with SARS-CoV-2 infection cytokine storms. In HIV coinfection, CD4⁺ T cells are corrupted, leading to exacerbated patient outcomes. Influenza coinfection decreases neutralization antibody efficacy and increases ACE2 receptors, overall boosting SARS-CoV-2 infection. For Mtb coinfection, both infections will affect the lung tissue, resulting in respiratory failure. In coinfection with parasites, Th2 and Treg cells are induced to suppress the immune system and ameliorate the intestinal inflammation severity of SARS-CoV-2.

Figure 4

T cells’ response in comorbid patients with SARS-CoV-2 infection. There is a disproportionate ratio of Th1/Th2 cells as well as lower populations of Th2 cells in asthmatic patients following SARS-CoV-2 infection. CD4 T lymphopenia is observed in hypertensive patients with SARS-CoV-2. Surface markers such as PD-1, HLA-DR, and CD38 are highly expressed while CD27 and CD28 are lightly expressed in CD8 T cells. In addition, there is a reduction in CD8 T cells and an elevation in CD4 T cells with cytokines IL-2, IL-6, IL-8, IL-10, IFNγ, and TGFβ in diabetic patients with SARS-CoV-2 infection.