NK cell receptor and ligand composition influences the clearance of SARS-CoV-2

Hsieh, Wan-Chen; Lai, En-Yu; Liu, Yuting; Wang, Yi‐Fu; Tzeng, Yi-Shiuan; Cui, Lü; Lai, Yun‐Ju; Huang, Hsiang-Chi; Huang, Jia-Hsin; Ni, Hung-Chih; Tsai, Dong-Yan; Liang, Jian-Jong; Liao, Chun-Che; Lu, Yating; Jiang, Laurence; Liu, Ming‐Tsan; Wang, Jann-Tay; Chang, Sui‐Yuan; Chen, Chung‐Yu; Tsai, Hsing-Chen; Chang, Yao-Ming; Wernig, Gerlinde; Li, Chia-Wei; Lin, Kuo‐I; Lin, Yi-Ling; Tsai, Huai-Kuang; Huang, Yen‐Tsung; Chen, Shih‐Yu

doi:10.1172/jci146408

Cited by 31 publications

(30 citation statements)

References 49 publications

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“…Finally, CD56 dim CD16 neg NK cells are unconventional CD56 dim cells whose cytotoxic capacity has been found to be lower compared to that of CD56 dim CD16 pos NK cells [32,33]. In this regard, the downregulation of CD16 expression has been also described in Herpes and Varicella zoster infections and might be associated with abnormal NK cell maturation during infection or prolonged cellular activity/activation, driving CD16 shedding, which might be a regulatory mechanism to prevent activation-induced cell death [34][35][36][37]. CD56 dim CD16 neg NK cells are considered to be the precursors of CD56 dim CD16 pos NK cells.…”

Section: Discussionmentioning

confidence: 99%

Expansion of CD56dimCD16neg NK Cell Subset and Increased Inhibitory KIRs in Hospitalized COVID-19 Patients

Casado

Moraga

Vizcarra

et al. 2021

Viruses

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Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) infection induces elevated levels of inflammatory cytokines, which are mainly produced by the innate response to the virus. The role of NK cells, which are potent producers of IFN-γ and cytotoxicity, has not been sufficiently studied in the setting of SARS-CoV-2 infection. We confirmed a different distribution of NK cell subsets in hospitalized COVID-19 patients despite their NK cell deficiency. The impairment of this innate defense is mainly focused on the cytotoxic capacity of the CD56dim NK cells. On the one hand, we found an expansion of the CD56dimCD16neg NK subset, lower cytotoxic capacities, and high frequencies of inhibitory 2DL1 and 2DL1/S1 KIR receptors in COVID-19 patients. On the other hand, the depletion of CD56dimCD16dim/bright NK cell subsets, high cytotoxic capacities, and high frequencies of inhibitory 2DL1 KIR receptors were found in COVID-19 patients. In contrast, no differences in the distribution of CD56bright NK cell subsets were found in this study. These alterations in the distribution and phenotype of NK cells might enhance the impairment of this crucial innate line of defense during COVID-19 infection.

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Section: Discussionmentioning

confidence: 99%

Expansion of CD56dimCD16neg NK Cell Subset and Increased Inhibitory KIRs in Hospitalized COVID-19 Patients

Casado

Moraga

Vizcarra

et al. 2021

Viruses

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“…Hsieh et al demonstrated that the cytolytic effects of NK cell function play an important role in SARS-CoV-2 clearance. In particular, NK cells that expressed receptor DNAM1 are linked to more rapid recovery [ 16 ].…”

Section: Implications Of Immune Modulation In Pregnancy and Sars-cov-2mentioning

confidence: 99%

SARS-CoV-2 and the Immune Response in Pregnancy with Delta Variant Considerations

Rangchaikul

Venketaraman

2021

Infectious Disease Reports

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As of September 2021, there has been a total of 123,633 confirmed cases of pregnant women with SARS-CoV-2 infection in the US according to the CDC, with maternal death being 2.85 times more likely, pre-eclampsia 1.33 times more likely, preterm birth 1.47 times more likely, still birth 2.84 times more likely, and NICU admission 4.89 times more likely when compared to pregnant women without COVID-19 infection. In our literature review, we have identified eight key changes in the immunological functioning of the pregnant body that may predispose the pregnant patient to both a greater susceptibility to SARS-CoV-2, as well as a more severe disease course. Factors that may impede immune clearance of SARS-CoV-2 include decreased levels of natural killer (NK) cells, Th1 CD4+ T cells, plasmacytoid dendritic cells (pDC), a decreased phagocytic index of neutrophil granulocytes and monocytes, as well as the immunomodulatory properties of progesterone, which is elevated in pregnancy. Factors that may exacerbate SARS-CoV-2 morbidity through hyperinflammatory states include increases in the complement system, which are linked to greater lung injury, as well as increases in TLR-1 and TLR-7, which are known to bind to the virus, leading to increased proinflammatory cytokines such as IL-6 and TNF-α, which are already elevated in normal pregnant physiology. Other considerations include an increase in angiotensin converting enzyme 2 (ACE2) in the maternal circulation, leading to increased viral binding on the host cell, as well as increased IL-6 and decreased regulatory T cells in pre-eclampsia. We also focus on how the Delta variant has had a concerning impact on SARS-CoV-2 cases in pregnancy, with an increased case volume and proportion of ICU admissions among the infected expecting mothers. We propose that the effects of the Delta variant are due to a combination of (1) the Delta variant itself being more transmissible, contagious, and efficient at infecting host cells, (2) initial evidence pointing to the Delta variant causing a significantly greater viral load that accumulates more rapidly in the respiratory system, (3) the pregnancy state being more susceptible to SARS-CoV-2 infection, as discussed in-depth, and (4) the lower rates of vaccination in pregnant women compared to the general population. In the face of continually evolving strains and the relatively low awareness of COVID-19 vaccination for pregnant women, it is imperative that we continue to push for global vaccine equity.

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“…For example, in a study of convalescent subjects with PCR proven SARS-CoV-2 infection using ELISpot, there were weak correlations between S antigen-specific T cell responses and neutralizing antibody titers to SARS-CoV-2 [ 41 ], Thus, it is important to better understand the roles of antibody and T cell responses, including IFN-γ and IL2, after vaccination [ 42 ], including in the hybrid immunity of subjects that were infected and then subsequently immunized with a COVID-19 vaccine [ 43 – 46 ], as well as their roles in multisystem inflammatory syndrome in children (MIS-C) and post-acute sequelae SARS-CoV-2 infection (PASC) [ 47 , 48 ]. Direct cytolytic clearance involving receptor-mediated interactions between immune cells and virus-infected cells suggested that natural killer (NK) cells expressing DNAM1 were increased in patients who more rapidly cleared from infection [ 49 ]. This suggests that NK cytolytic responses are related to the clearance of SARS-CoV-2 [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

CHARM: COVID-19 Health Action Response for Marines–Association of antigen-specific interferon-gamma and IL2 responses with asymptomatic and symptomatic infections after a positive qPCR SARS-CoV-2 test

et al. 2022

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SARS-CoV-2 T cell responses are associated with COVID-19 recovery, and Class I- and Class II-restricted epitopes have been identified in the spike (S), nucleocapsid (N) and membrane (M) proteins and others. This prospective COVID-19 Health Action Response for Marines (CHARM) study enabled assessment of T cell responses against S, N and M proteins in symptomatic and asymptomatic SARS-CoV-2 infected participants. At enrollment all participants were negative by qPCR; follow-up occurred biweekly and bimonthly for the next 6 weeks. Study participants who tested positive by qPCR SARS-CoV-2 test were enrolled in an immune response sub-study. FluoroSpot interferon-gamma (IFN-γ) and IL2 responses following qPCR-confirmed infection at enrollment (day 0), day 7 and 14 and more than 28 days later were measured using pools of 17mer peptides covering S, N, and M proteins, or CD4+CD8 peptide pools containing predicted epitopes from multiple SARS-CoV-2 antigens. Among 124 asymptomatic and 105 symptomatic participants, SARS-CoV-2 infection generated IFN-γ responses to the S, N and M proteins that persisted longer in asymptomatic cases. IFN-γ responses were significantly (p = 0.001) more frequent to the N pool (51.4%) than the M pool (18.9%) among asymptomatic but not symptomatic subjects. Asymptomatic IFN-γ responders to the CD4+CD8 pool responded more frequently to the S pool (55.6%) and N pool (57.1%), than the M pool (7.1%), but not symptomatic participants. The frequencies of IFN-γ responses to the S and N+M pools peaked 7 days after the positive qPCR test among asymptomatic (S pool: 22.2%; N+M pool: 28.7%) and symptomatic (S pool: 15.3%; N+M pool 21.9%) participants and dropped by >28 days. Magnitudes of post-infection IFN-γ and IL2 responses to the N+M pool were significantly correlated with IFN-γ and IL2 responses to the N and M pools. These data further support the central role of Th1-biased cell mediated immunity IFN-γ and IL2 responses, particularly to the N protein, in controlling COVID-19 symptoms, and justify T cell-based COVID-19 vaccines that include the N and S proteins.

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NK cell receptor and ligand composition influences the clearance of SARS-CoV-2

Cited by 31 publications

References 49 publications

Expansion of CD56dimCD16neg NK Cell Subset and Increased Inhibitory KIRs in Hospitalized COVID-19 Patients

Expansion of CD56dimCD16neg NK Cell Subset and Increased Inhibitory KIRs in Hospitalized COVID-19 Patients

SARS-CoV-2 and the Immune Response in Pregnancy with Delta Variant Considerations

CHARM: COVID-19 Health Action Response for Marines–Association of antigen-specific interferon-gamma and IL2 responses with asymptomatic and symptomatic infections after a positive qPCR SARS-CoV-2 test

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