Biology subjects

Zayou, L.

Publications and source records attributed to Zayou, L..

3 recordsLinked to original sources

bioRxiv2022

High Frequencies of Phenotypically and Functionally Senescent and Exhausted CD56+CD57+PD-1+ Natural Killer Cells, SARS-CoV-2-Specific Memory CD4+ and CD8+ T cells Associated with Severe Disease in Unvaccinated COVID-19 Patients

Unvaccinated COVID-19 patients display a large spectrum of symptoms, ranging from asymptomatic to severe symptoms, the latter even causing death. Distinct Natural killer (NK) and CD4+ and CD8+ T cells immune responses are generated in COVID-19 patients. However, the phenotype and functional characteristics of NK cells and T-cells associated with COVID-19 pathogenesis versus protection remain to be elucidated. In this study, we compared the phenotype and function of NK cells SARS-CoV-2-specific CD4+ and CD8+ T cells in unvaccinated symptomatic (SYMP) and unvaccinated asymptomatic (ASYMP) COVID-19 patients. The expression of senescent CD57 marker, CD45RA/CCR7differentiation status, exhaustion PD-1 marker, activation of HLA-DR, and CD38 markers were assessed on NK and T cells from SARS-CoV-2 positive SYMP patients, ASYMP patients, and Healthy Donors (HD) using multicolor flow cytometry. We detected significant increases in the expression levels of both exhaustion and senescence markers on NK and T cells from SYMP patients compared to ASYMP patients and HD controls. In SYMP COVID-19 patients, the T cell compartment displays several alterations involving naive, central memory, effector memory, and terminally differentiated T cells. The senescence CD57 marker was highly expressed on CD8+ TEM cells and CD8+ TEMRA cells. Moreover, we detected significant increases in the levels of proinflammatory TNF-, IFN-{gamma}, IL-6, IL-8, and IL-17 cytokines from SYMP COVID-19 patients, compared to ASYMP COVID-19 patients and HD controls. The findings suggest exhaustion and senescence in both NK and T cell compartment is associated with severe disease in critically ill COVID-19 patients. IMPORTANCEUnvaccinated COVID-19 patients display a large spectrum of symptoms, ranging from asymptomatic to severe symptoms, the latter even causing death. Distinct Natural killer (NK) and CD4+ and CD8+ T cells immune responses are generated in COVID-19 patients. In this study, we detected significant increases in the expression levels of both exhaustion and senescence markers on NK and T cells from unvaccinated symptomatic (SYMP) compared to unvaccinated asymptomatic (ASYMP) COVID-19 patients. Moreover, we detected significant increases in the levels of proinflammatory TNF-, IFN-{gamma}, IL-6, IL-8, and IL-17 cytokines from SYMP COVID-19 patients, compared to ASYMP COVID-19 patients. The findings suggest exhaustion and senescence in both NK and T cell compartment is associated with severe disease in critically ill COVID-19 patients. TWEETSignificant exhaustion and senescence in both NK and T cells were detected in unvaccinated symptomatic COVID-19 patients, suggesting a weakness in both innate and adaptive immune systems leads to severe disease in critically ill COVID-19 patients.

immunology↗

bioRxiv2022

A Prime/Pull RR2/CXCL11 Therapeutic Vaccine that Bolsters the Number and Function of Dorsal Root Ganglia Tissue-Resident HSV-Specific CD8+ TRM Cells Protects Latently Infected Guinea Pigs from Recurrent Genital Herpes

Reactivation of herpes simplex virus type 2 (HSV-2) from latently infected dorsal root ganglia (DRG) and subsequent virus shedding in the genital tract trigger recurrent genital herpes. Memory CD8+ T cells play a critical role in preventing HSV-2 reactivation from latently infected DRG, thus reducing recurrent genital lesions. The role of T-cell attracting chemokines in promoting CD8+ T cell protective immunity in recurrent genital herpes remains to be fully elucidated. In this study, we investigated whether and how the CXCL11/CXCR3 pathway affects the frequency and function of DRG-resident CD8+ T cells and the severity of recurrent genital herpes. Latently infected guinea pigs were primed with the HSV-1 RR2 protein, delivered intramuscularly with CpG/Alum adjuvants, and the induced T cells were "pulled" from the periphery into the latently infected DRG using T-cell attracting CXCL11 chemokine, delivered to DRG. In the guinea pigs that received the prime/pull vaccine, we detected a significant increase in both the number and function of tissue-resident IFN-{gamma}+CD103+CD44+CXCR3+CD8+ TRM cells that infiltrated healed sites of the vaginal mucosa (VM) and DRG tissues. This was associated with a significant decrease in virus shedding and a reduction in both the severity and frequency of recurrent genital herpes lesions. In contrast, in the guinea pigs that received the RR2 vaccine alone, we detected fewer functional CD8+ TRM cells and no reduction in the severity of recurrent genital herpes. These findings highlight the role of the CXCL11/CXCR3 chemokine pathway in shaping tissue-resident CD8+ TRM cell protective immunity against recurrent genital herpes. IMPORTANCERecurrent genital herpes is a common sexually transmitted disease worldwide. Currently, no FDA-approved therapeutic vaccines are available. In the present study, we used HSV-2 latently infected guinea pig to investigate a novel therapeutic prime/pull vaccine strategy based on priming T cells systemically, with a recombinantly expressed herpes envelope and tegument protein RR2 and "pulling" primed T cells into the tissues of latently infected ganglia with the T-cell-attracting chemokine, CXCL11. We discovered that this RR2/CXCL11 prime/pull vaccine elicited a significant reduction in virus shedding and a decrease in both the severity and frequency of recurrent genital herpes sores. This protection correlated with increased numbers of functional tissue-resident IFN-{gamma}+CD103+CD44+CXCR3+CD8+ TRM cells that infiltrate healed sites of the VM tissues and DRG. Our findings shed light on the role of TRM cells in protection against recurrent genital herpes and propose the prime/pull therapeutic vaccine as a new strategy against genital herpes. TWEETThe present study presents a novel RR2/CXCL11 prime/pull therapeutic vaccine that elicited a significant reduction in virus shedding and a decrease in both the severity and frequency of recurrent genital herpes sores.

immunology↗

bioRxiv2022

High Frequencies of PD-1+TIM3+TIGIT+CTLA4+ Functionally Exhausted SARS-CoV-2-Specific CD4+ and CD8+ T Cells Associated with Severe Disease in Critically ill COVID-19 Patients

SARS-CoV-2-specific memory T cells that cross-react with common cold coronaviruses (CCCs) are present in both healthy donors and COVID-19 patients. However, whether these cross-reactive T cells play a role in COVID-19 pathogenesis versus protection remain to be fully elucidated. In this study, we characterized cross-reactive SARS-CoV-2-specific CD4+ and CD8+ T cells, targeting genome-wide conserved epitopes in a cohort of 147 non-vaccinated COVID-19 patients, divided into six groups based on the degrees of disease severity. We compared the frequency, phenotype, and function of these SARS-CoV-2-specific CD4+ and CD8+ T cells between severely ill and asymptomatic COVID-19 patients and correlated this with -CCCs and {beta}-CCCs co-infection status. Compared with asymptomatic COVID-19 patients, the severely ill COVID-19 patients and patients with fatal outcomes: (i) Presented a broad leukocytosis and a broad CD4+ and CD8+ T cell lymphopenia; (ii) Developed low frequencies of functional IFN-{gamma}-producing CD134+CD138+CD4+ and CD134+CD138+CD8+ T cells directed toward conserved epitopes from structural, non-structural and regulatory SARS-CoV-2 proteins; (iii) Displayed high frequencies of SARS-CoV-2-specific functionally exhausted PD-1+TIM3+TIGIT+CTLA4+CD4+ and PD-1+TIM3+TIGIT+CTLA4+CD8+ T cells; and (iv) Displayed similar frequencies of co-infections with {beta}-CCCs strains but significantly fewer co-infections with -CCCs strains. Interestingly, the cross-reactive SARS-CoV-2 epitopes that recalled the strongest CD4+ and CD8+ T cell responses in unexposed healthy donors (HD) were the most strongly associated with better disease outcome seen in asymptomatic COVID-19 patients. Our results demonstrate that, the critically ill COVID-19 patients displayed fewer co-infection with -CCCs strain, presented broad T cell lymphopenia and higher frequencies of cross-reactive exhausted SARS-CoV-2-specific CD4+ and CD8+ T cells. In contrast, the asymptomatic COVID-19 patients, appeared to present more co-infections with -CCCs strains, associated with higher frequencies of functional cross-reactive SARS-CoV-2-specific CD4+ and CD8+ T cells. These findings support the development of broadly protective, T-cell-based, multi-antigen universal pan-Coronavirus vaccines. KEY POINTSO_LIA broad lymphopenia and lower frequencies of SARS-CoV-2-specific CD4+ and CD8+ T-cells were associated with severe disease onset in COVID-19 patients. C_LIO_LIHigh frequencies of phenotypically and functionally exhausted SARS-CoV-2-specific CD4+ and CD8+ T cells, co-expressing multiple exhaustion markers, and targeting multiple structural, non-structural, and regulatory SARS-CoV-2 protein antigens, were detected in severely ill COVID-19 patients. C_LIO_LICompared to severely ill COVID-19 patients and to patients with fatal outcomes, the (non-vaccinated) asymptomatic COVID-19 patients presented more functional cross-reactive CD4+ and CD8+ T cells targeting conserved epitopes from structural, non-structural, and regulatory SARS-CoV-2 protein antigens. C_LIO_LIThe cross-reactive SARS-CoV-2 epitopes that recalled the strongest CD4+ and CD8+ T cell responses in unexposed healthy donors (HD) were the most strongly associated with better disease outcomes seen in asymptomatic COVID-19 patients. C_LIO_LICompared to severely ill COVID-19 patients and to patients with fatal outcomes, the (non-vaccinated) asymptomatic COVID-19 patients presented higher rates of co-infection with the -CCCs strains. C_LIO_LICompared to patients with mild or asymptomatic COVID-19, severely ill symptomatic patients and patients with fatal outcomes had more exhausted SARS-CoV-2-speccific CD4+ and CD8+ T cells that preferentially target cross-reactive epitopes that share high identity and similarity with the {beta}-CCCs strains. C_LI

immunology↗