Biology subjects

Khatri, B.

Publications and source records attributed to Khatri, B..

6 recordsLinked to original sources

bioRxiv2023

Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland

Fine mapping and bioinformatic analysis of the DDX6-CXCR5 genetic risk association in Sjogrens Disease (SjD) and Systemic Lupus Erythematosus (SLE) identified five common SNPs with functional evidence in immune cell types: rs4938573, rs57494551, rs4938572, rs4936443, rs7117261. Functional interrogation of nuclear protein binding affinity, enhancer/promoter regulatory activity, and chromatin-chromatin interactions in immune, salivary gland epithelial, and kidney epithelial cells revealed cell type-specific allelic effects for all five SNPs that expanded regulation beyond effects on DDX6 and CXCR5 expression. Mapping the local chromatin regulatory network revealed several additional genes of interest, including lnc-PHLDB1-1. Collectively, functional characterization implicated the risk alleles of these SNPs as modulators of promoter and/or enhancer activities that regulate cell type-specific expression of DDX6, CXCR5, and lnc-PHLDB1-1, among others. Further, these findings emphasize the importance of exploring the functional significance of SNPs in the context of complex chromatin architecture in disease-relevant cell types and tissues.

genetics↗

bioRxiv2023

Establishment of Tuberculosis Meningitis Mouse Model Using Aerosol Route of W. Beijing HN878 strain

In this study, we report the development of a tuberculosis meningitis (TBM) mouse model using the HN878 strain via the aerosol route. Three genetically different strains of mice, CB6F1, C57BL/6 and BALB/c mice, were used to determine the dissemination of HN878 in the brain. The 8 x 108 CFU/ml of HN878 dose was used to infect CB6F1 mice and deposited approximately 3.8 (0.07, SD) log10 CFU in the lungs. The burden of HN878 in the brain of the control group (administered saline) after approximately 16/17 days post-infection for CB6F1, C57BL/6 and BALB/c were 4.00 (0.47 SD), 3.79 (0.27, SD) and 2.12 (0.41, SD) log10 CFU/brain, respectively. The log10 CFU/brain in the BCG vaccinated CB6F1, C57BL/6 and BALB/c mice were 1.05 (0.61, SD), 2.13 (0.33, SD) and 1.42 (0.38, SD) respectively, which, if compared to the control groups, BCG vaccinated mice inhibited dissemination of HN878 in the brain by an impressive 2.94 (CB6F1), 1.66 (C57BL/6) and 0.69 (BALB/c) log10 CFU/brain reduction. In conclusion, we have established a relatively inexpensive TBM mouse model using an aerosol, a natural route of infection, which will advance research in understanding TBM dissemination to the brain, and preclinical tuberculosis vaccine/drug discovery/drug regimens against TBM.

developmental biology↗

bioRxiv2022

Ancestral origins are associated with SARS-CoV-2 susceptibility and protection in a Florida patient population

COVID-19 is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The severity of COVID-19 is highly variable and related to known (e.g., age, obesity, immune deficiency) and unknown risk factors. The widespread clinical symptoms encompass a large group of asymptomatic COVID-19 patients, raising a crucial question regarding genetic susceptibility, e.g., whether individual differences in immunity play a role in patient symptomatology and how much human leukocyte antigen (HLA) contributes to this. To reveal genetic determinants of susceptibility to COVID-19 severity in the population and further explore potential immune-related factors, we performed a genome-wide association study on 284 confirmed COVID-19 patients (cases) and 95 healthy individuals (controls). We compared cases and controls of European (EUR) ancestry and African American (AFR) ancestry separately. We identified two loci on chromosomes 5q32 and 11p12, which reach the significance threshold of suggestive association (p<1x10-5 threshold adjusted for multiple trait testing) and are associated with the COVID-19 susceptibility in the European ancestry (index rs17448496: odds ratio [OR] = 0.173; 95% confidence interval [CI], 0.08-0.36 for G allele; p=5.15x 10-5 and index rs768632395: OR = 0.166; 95% CI, 0.07-0.35 for A allele; p= 4.25x10-6, respectively), which were associated with two genes, PPP2R2B at 5q32, and LRRC4C at 11p12, respectively. To explore the linkage between HLA and COVID-19 severity, we applied fine-mapping analysis to dissect the HLA association with mild and severe cases. Using In-silico binding predictions to map the binding of risk/protective HLA to the viral structural proteins, we found the differential presentation of viral peptides in both ancestries. Lastly, extrapolation of the identified HLA from the cohort to the worldwide population revealed notable correlations. The study uncovers possible differences in susceptibility to COVID-19 in different ancestral origins in the genetic background, which may provide new insights into the pathogenesis and clinical treatment of the disease.

genetics↗

bioRxiv2020

Efficacy and immunogenicity of different BCG doses in BALB/c and CB6F1 mice when challenged with H37Rv or Beijing HN878

In this study, 2 strains of mice (BALB/c and CB6F1) were vaccinated with a range of Bacille Calmette-Guerin (BCG) Danish doses from 3x105 to 30 CFU/mouse, followed by either immunogenicity evaluation or aerosol infection with Mycobacterium tuberculosis (a laboratory strain H37Rv or West-Beijing HN878 strain). The results indicated that both strains of mice when infected with HN878 exhibited significant protection in their lungs with BCG doses at 3x105 - 3000 CFU (BALB/c) and 3x105-300 CFU (CB6F1). Whereas, both strains of mice when infected with H37Rv, significant protection was seen in BCG doses at 3x105 - 300 CFU. Immunological evaluation revealed interesting results; i) both strains of mice demonstrated a significant increase in the frequencies of BCG-specific IFN{gamma}+ IL2+ TNF+ CD4 T cells in the BCG doses at 3x105 - 3000 CFU (BALB/c) and 3x105 - 300 CFU (CB6F1); ii) secretion of IL2 and IFN{gamma} were correlated with the bacterial burden in the lungs of HN878 infected CB6F1 mice. The study demonstrated a BCG dose at 3000 CFU (an equivalent single human dose in the mice by body weight index) is protective in both strains of mice and the use of a virulent clinical isolate in testing new tuberculosis vaccine/advancing research is recommended.

immunology↗

bioRxiv2018

Antibiotic resistance evasion is explained by rare mutation frequency and not by lack of compensatory mechanisms

Drug resistant infections represent one of the most challenging medical problems of our time. D-cycloserine is an antibiotic used for decades without appearance and dissemination of antibiotic resistant strains, making it an ideal model compound to understand what drives resistance evasion. We investigated why Mycobacterium tuberculosis fails to become resistant to D-cycloserine. To address this question we employed a combination of bacterial genetics, genomics, biochemistry and fitness analysis in vitro, in macrophages and in mice. Altogether, our results suggest that the ultra-low mutation frequency associated with D-cycloserine resistance is the dominant factor delaying the appearance of clinical resistance to this antibiotic in bacteria infecting humans, and not lack of potential compensatory mechanisms.\n\nOne Sentence SummaryWe show that the lack of D-cycloserine resistance in Mycobacterium tuberculosis is due its ultra-low mutation frequency rather than lack of compensatory mechanisms.

microbiology↗

bioRxiv2017

Experimental infection of cattle with Mycobacterium tuberculosis isolates shows the attenuation of the human tubercle bacillus for cattle

The Mycobacterium tuberculosis complex (MTBC) is the collective term given to the group of bacteria that cause tuberculosis (TB) in mammals. It has been reported that M. tuberculosis H37Rv, a standard reference MTBC strain, is attenuated in cattle compared to Mycobacterium bovis. However, as M. tuberculosis H37Rv was isolated in the early 1930s, and genetic variants are known to exist, we sought to revisit this question of attenuation of M. tuberculosis for cattle by performing a bovine experimental infection with a recent M. tuberculosis isolate. Here we report infection of cattle using M. bovis AF2122/97, M. tuberculosis H37Rv, and M. tuberculosis BTB1558, the latter isolated in 2008 during a TB surveillance project in Ethiopian cattle. We show that both M. tuberculosis strains caused reduced gross and histopathology in cattle compared to M. bovis. Using M. tuberculosis H37Rv and M. bovis AF2122/97 as the extremes in terms of infection outcome, we used RNA-Seq analysis to explore differences in the peripheral response to infection as a route to identify biomarkers of progressive disease in contrast to a more quiescent, latent infection. Our work shows the attenuation of M. tuberculosis strains for cattle, and emphasizes the potential of the bovine model as a One Health approach to inform human TB biomarker development and post-exposure vaccine development.

immunology↗