Biology subjects

Presti, R. M.

Publications and source records attributed to Presti, R. M..

4 recordsLinked to original sources

bioRxiv2021

SARS-CoV-2 mRNA vaccination elicits robust and persistent T follicular helper cell response in humans

SARS-CoV-2 mRNA vaccines induce robust anti-spike (S) antibody and CD4+ T cell responses. It is not yet clear whether vaccine-induced follicular helper CD4+ T (TFH) cell responses contribute to this outstanding immunogenicity. Using fine needle aspiration of draining axillary lymph nodes from individuals who received the BNT162b2 mRNA vaccine, we show that frequency of TFH correlates with that of S-binding germinal center B cells. Mining of the responding TFH T cell receptor repertoire revealed a strikingly immunodominant HLADPB1* 04-restricted response to S167-180 in individuals with this allele, which is among the most common HLA alleles in humans. Paired blood and lymph node specimens show that while circulating S-specific TFH cells peak one week after the second immunization, S-specific TFH persist at nearly constant frequencies for at least six months. Collectively, our results underscore the key role that robust TFH cell responses play in establishing long-term immunity by this efficacious human vaccine.

immunology↗

bioRxiv2021

A public vaccine-induced human antibody protects against SARS-CoV-2 and emerging variants

The emergence of antigenically distinct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with increased transmissibility is a public health threat. Some of these variants show substantial resistance to neutralization by SARS-CoV-2 infection- or vaccination-induced antibodies, which principally target the receptor binding domain (RBD) on the virus spike glycoprotein. Here, we describe 2C08, a SARS-CoV-2 mRNA vaccine-induced germinal center B cell-derived human monoclonal antibody that binds to the receptor binding motif within the RBD. 2C08 broadly neutralizes SARS-CoV-2 variants with remarkable potency and reduces lung inflammation, viral load, and morbidity in hamsters challenged with either an ancestral SARS-CoV-2 strain or a recent variant of concern. Clonal analysis identified 2C08-like public clonotypes among B cell clones responding to SARS-CoV-2 infection or vaccination in at least 20 out of 78 individuals. Thus, 2C08-like antibodies can be readily induced by SARS-CoV-2 vaccines and mitigate resistance by circulating variants of concern. One Sentence SummaryProtection against SARS-CoV-2 variants by a potently neutralizing vaccine-induced human monoclonal antibody.

immunology↗

bioRxiv2021

Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection.

Complement activation has been implicated in the pathogenesis of severe SARS-CoV-2 infection. However, it remains to be determined whether increased complement activation is a broad indicator of critical illness (and thus, no different in COVID-19). It is also unclear which pathways are contributing to complement activation in COVID-19, and, if complement activation is associated with certain features of severe SARS-CoV-2 infection, such as endothelial injury and hypercoagulability. To address these questions, we investigated complement activation in the plasma from patients with COVID-19 prospectively enrolled at two tertiary care centers. We compared our patients to two non-COVID cohorts: (a) patients hospitalized with influenza, and (b) patients admitted to the intensive care unit (ICU) with acute respiratory failure requiring invasive mechanical ventilation (IMV). We demonstrate that circulating markers of complement activation (i.e., sC5b-9) are elevated in patients with COVID-19 compared to those with influenza and to patients with non-COVID-19 respiratory failure. Further, the results facilitate distinguishing those who are at higher risk of worse outcomes such as requiring ICU admission, or IMV. Moreover, the results indicate enhanced activation of the alternative complement pathway is most prevalent in patients with severe COVID-19 and is associated with markers of endothelial injury (i.e., Ang2) as well as hypercoagulability (i.e., thrombomodulin and von Willebrand factor). Our findings identify complement activation to be a distinctive feature of COVID-19, and provide specific targets that may be utilized for risk prognostication, drug discovery and personalized clinical trials. SUMMMARYComplement has been implicated in COVID-19. However, whether this is distinctive of COVID-19 remains unanswered. Ma et al report increased complement activation in COVID-19 compared to influenza and non-COVID respiratory failure, and demonstrate alternative pathway activation as a key marker of multiorgan failure and death.

immunology↗

bioRxiv2020

CARD8 inflammasome mediates pyroptosis of HIV-1-infected cells by sensing viral protease activity

HIV-1 has high mutation rates and exists as mutant swarms in the host. Rapid evolution of HIV-1 allows the virus to outpace host immune system, leading to viral persistence. Novel approaches to target immutable components are needed to clear HIV-1 infection. Here we report a pattern-recognition receptor CARD8 that senses enzymatic activity of the HIV-1 protease, which is indispensable for the virus. All subtypes of HIV-1 can be sensed by CARD8 despite substantial viral diversity. HIV-1 evades CARD8 sensing because the viral protease remains inactive in infected cells prior to viral budding. Induction of premature intracellular activation of the viral protease triggers CARD8 inflammasome-mediated pyroptosis of HIV-1-infected cells. This strategy leads to clearance of latent HIV-1 in patient CD4+ T cells after virus reactivation. Taken together, our study identifies CARD8 as an inflammasome sensor of HIV-1 that holds promise as a strategy for clearance of persistent HIV-1 infection.

immunology↗