Noton K. Dutta

Bio: Noton K. Dutta is an academic researcher from Johns Hopkins University School of Medicine. The author has contributed to research in topics: Tuberculosis & Mycobacterium tuberculosis. The author has an hindex of 30, co-authored 90 publications receiving 2605 citations. Previous affiliations of Noton K. Dutta include Johns Hopkins University & Seoul National University.

The Nucleocapsid Protein of SARS-CoV-2: a Target for Vaccine Development.

Abstract: During the current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS–CoV-2), there has been an unprecedented level of global collaboration that has led to a rapid characterization of SARS–CoV-2 (1). Its sequence shares 79.6% identity to SARS–CoV (1, 2), the infectious virus that caused an epidemic in 2003 (2, 3). SARS–CoV-2 has a single-stranded, plus-sense, RNA genome of approximately 30 kb, which includes five major open reading frames encoding nonstructural replicase polyproteins and structural proteins (1), namely, spike (S) (4–6), envelope (E), membrane (M), and nucleocapsid (N) (7), and they are in the same order and of approximately the same sizes as those in SARS-CoV. The SARS–CoV-2 S protein is being used as the leading target antigen in vaccine development (8, 9). However, the complex molecular details of viral entry may lead to complications with the vaccine response, similar to those seen with HIV type 1 (HIV-1) Env protein vaccine efforts (10). The SARS–CoV-2 S gene has 76% amino acid similarity to the SARS-CoV S gene (11), and nonsynonymous mutations developed in the S protein as the SARS-CoV epidemic progressed (12, 13). In contrast, the N gene is more conserved and stable, with 90% amino acid homology and fewer mutations over time (2, 3, 11, 14–16). N proteins of many coronaviruses are highly immunogenic and are expressed abundantly during infection (17). High levels of IgG antibodies against N have been detected in sera from SARS patients (18), and the N protein is a representative antigen for the T-cell response in a vaccine setting, inducing SARS-specific T-cell proliferation and cytotoxic activity (19, 20). We have already shown that the middle or C-terminal region of the SARS-CoV N protein is important for eliciting antibodies against SARS-CoV during the immune response (21–23). New reports have additionally shown that the crystal structure of the SARS–CoV-2 nucleocapsid protein is similar to those of previously described coronavirus N proteins, but their surface electrostatic potential characteristics are distinct (7). Sheikh et al. studied the factors influencing N gene variations among 13 coronaviruses and how these affect virus-host relationships, reporting a high AT% and low GC% in the nucleotide contents of SARS coronavirus (24). In this issue, Cong et al. (17) used a mouse hepatitis virus (MHV) model to show that the viral nucleocapsid (N) protein contributes to forming helical ribonucleoproteins during the packaging of the RNA genome, regulating viral RNA synthesis during replication and transcription and modulating metabolism in infected subjects. This study complements others that have shown N to have multiple functions (25). It is becoming more evident just how critical this protein is for multiple steps of the viral life cycle. These reports offer important and timely insights relevant to the SARS–CoV-2 N protein, a vaccine target that has some distinct advantages over other potential SARS– CoV-2 antigens. Because of the conservation of the N protein sequence, the expanding Citation Dutta NK, Mazumdar K, Gordy JT. 2020. The nucleocapsid protein of SARS–CoV-2: a target for vaccine development. J Virol 94:e00647-20. https://doi.org/10.1128/JVI.00647-20. Editor Rebecca Ellis Dutch, University of Kentucky College of Medicine Copyright © 2020 American Society for Microbiology. All Rights Reserved. Address correspondence to Noton K. Dutta, ndutta1@jhmi.edu Published LETTER TO THE EDITOR

Latent Tuberculosis Infection: Myths, Models, and Molecular Mechanisms

Abstract: SUMMARY The aim of this review is to present the current state of knowledge on human latent tuberculosis infection (LTBI) based on clinical studies and observations, as well as experimental in vitro and animal models. Several key terms are defined, including “latency,” “persistence,” “dormancy,” and “antibiotic tolerance.” Dogmas prevalent in the field are critically examined based on available clinical and experimental data, including the long-held beliefs that infection is either latent or active, that LTBI represents a small population of nonreplicating, “dormant” bacilli, and that caseous granulomas are the haven for LTBI. The role of host factors, such as CD4 + and CD8 + T cells, T regulatory cells, tumor necrosis factor alpha (TNF-α), and gamma interferon (IFN-γ), in controlling TB infection is discussed. We also highlight microbial regulatory and metabolic pathways implicated in bacillary growth restriction and antibiotic tolerance under various physiologically relevant conditions. Finally, we pose several clinically important questions, which remain unanswered and will serve to stimulate future research on LTBI.

Genetic Requirements for the Survival of Tubercle Bacilli in Primates

Abstract: Background TB leads to the annual death of 1.7 million people. The failure of the BCG vaccine, synergy between AIDS and TB, and the emergence of drug-resistance have worsened this situation. It is imperative to delineate the mechanisms employed by Mtb to successfully infect and persist in mammalian lungs.

Transcriptional reprogramming in nonhuman primate (rhesus macaque) tuberculosis granulomas.

Abstract: Background: In response to Mtb infection, the host remodels the infection foci into a dense mass of cells known as the granuloma. The key objective of the granuloma is to contain the spread of Mtb into uninfected regions of the lung. However, it appears that Mtb has evolved mechanisms to resist killing in the granuloma. Profiling granuloma transcriptome will identify key immune signaling pathways active during TB infection. Such studies are not possible in human granulomas, due to various confounding factors. Nonhuman Primates (NHPs) infected with Mtb accurately reflect human TB in clinical and pathological contexts. Methodology/Principal Findings: We studied transcriptomics of granuloma lesions in the lungs of NHPs exhibiting active TB, during early and late stages of infection. Early TB lesions were characterized by a highly pro-inflammatory environment, expressing high levels of immune signaling pathways involving IFNc, TNFa, JAK, STAT and C-C/C-X-C chemokines. Late TB lesions, while morphologically similar to the early ones, exhibited an overwhelming silencing of the inflammatory response. Reprogramming of the granuloma transcriptome was highly significant. The expression of , two-thirds of all genes induced in early lesions was later repressed. Conclusions/Significance: The transcriptional characteristics of TB granulomas undergo drastic changes during the course of infection. The overwhelming reprogramming of the initial pro-inflammatory surge in late lesions may be a host strategy to limit immunopathology. We propose that these host profiles can predict changes in bacterial replication and physiology, perhaps serving as markers for latency and reactivation.

The spike protein of SARS-CoV — a target for vaccine and therapeutic development

Abstract: Severe acute respiratory syndrome (SARS) is a newly emerging infectious disease caused by a novel coronavirus, SARS-coronavirus (SARS-CoV). The SARS-CoV spike (S) protein is composed of two subunits; the S1 subunit contains a receptor-binding domain that engages with the host cell receptor angiotensin-converting enzyme 2 and the S2 subunit mediates fusion between the viral and host cell membranes. The S protein plays key parts in the induction of neutralizing-antibody and T-cell responses, as well as protective immunity, during infection with SARS-CoV. In this Review, we highlight recent advances in the development of vaccines and therapeutics based on the S protein.