A5086413795- Tuberculosis Research and Epidemiology
- Vector-borne infectious diseases
- Mosquito-borne diseases and control
- Immune responses and vaccinations
- Toxoplasma gondii Research Studies
- Immunodeficiency and Autoimmune Disorders
- Mycobacterium research and diagnosis
- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Immune Response and Inflammation
- Viral Infections and Vectors
- Extracellular vesicles in disease
- Bacterial biofilms and quorum sensing
- Single-cell and spatial transcriptomics
- SARS-CoV-2 and COVID-19 Research
- Culinary Culture and Tourism
- Bone Metabolism and Diseases
- Thermal Regulation in Medicine
- Cell death mechanisms and regulation
- Inflammasome and immune disorders
- Intensive Care Unit Cognitive Disorders
- Trace Elements in Health
- Cannabis and Cannabinoid Research
- Bacterial Genetics and Biotechnology
- Food Security and Health in Diverse Populations
University of Pittsburgh
2019-2025
University of Arkansas for Medical Sciences
2014-2018
Trudeau Institute
2010
There is pressing urgency to understand the pathogenesis of severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes disease COVID-19. SARS-CoV-2 spike (S) protein binds angiotensin-converting enzyme (ACE2), and in concert with host proteases, principally transmembrane serine protease (TMPRSS2), promotes cellular entry. The cell subsets targeted by tissues factors that regulate ACE2 expression remain unknown. Here, we leverage human, non-human primate, mouse...
Mycobacterium tuberculosis lung infection results in a complex multicellular structure: the granuloma. In some granulomas, immune activity promotes bacterial clearance, but others, bacteria persist and grow. We identified correlates of control cynomolgus macaque granulomas by co-registering longitudinal positron emission tomography computed imaging, single-cell RNA sequencing, measures clearance. Bacterial persistence occurred enriched for mast, endothelial, fibroblast, plasma cells,...
Tuberculosis (TB) is a major health burden worldwide despite widespread intradermal (ID) BCG vaccination in newborns. We previously demonstrated that changing the route and dose from 5 × 105 CFUs ID to 107 i.v. resulted prevention of Mycobacterium tuberculosis (Mtb) infection TB disease highly susceptible nonhuman primates. Identifying immune mechanisms protection following will facilitate development more effective vaccines against TB. Here, we depleted lymphocyte subsets prior during Mtb...
There is pressing urgency to better understand the pathogenesis of severe acute respiratory syndrome (SARS) coronavirus (CoV) clade SARS-CoV-2. SARS-CoV-2, like SARS-CoV, utilizes ACE2 bind host cells. While initial SARS-CoV-2 cell entry and infection depend on in concert with protease TMPRSS2 for spike (S) protein activation, specific subsets targeted by tissues, factors that regulate expression, remain unknown. Here, we leverage human non-human primate (NHP) single-cell RNA-sequencing...
The functional role of CD8+ lymphocytes in tuberculosis remains poorly understood. We depleted innate and/or adaptive macaques and showed that loss all CD8α+ cells (using anti-CD8α antibody) significantly impaired early control Mycobacterium (Mtb) infection, leading to increased granulomas, lung inflammation, bacterial burden. Analysis barcoded Mtb from infected demonstrated depletion allowed establishment lungs dissemination within lymph nodes, while only T (with anti-CD8β worsened nodes....
Mutations of the Plekhm1 gene in humans and rats cause osteopetrosis, an inherited bone disease characterized by diminished resorption osteoclasts. PLEKHM1 binds to RAB7 is critical for lysosome trafficking. However, molecular mechanisms which regulates lysosomal pathways remain unknown. Here, we generated germline conditional Plekhm1-deficient mice. These mice displayed no overt abnormalities major organs, except increase trabecular mass. Furthermore, loss abrogated peripheral distribution...
Coxiella burnetii is an intracellular Gram-negative bacterium that causes human Q fever, a flu-like disease can progress to chronic, life-threatening endocarditis. In humans, C. infects alveolar macrophages and promotes phagosomal fusion with autophagosomes lysosomes, establishing unique parasitophorous vacuole (PV) in which replicate. The pathogen uses Dot/Icm type IV secretion system (T4SS) deliver effector proteins the host cytoplasm, where they alter cellular processes benefit pathogen....
In 2017 over 550,000 estimated new cases of multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) occurred, emphasizing a need for treatment strategies. Linezolid (LZD) is potent antibiotic drug-resistant Gram-positive infections and an effective TB. However, extended LZD use can lead to LZD-associated host toxicities, most commonly bone marrow suppression. toxicities may be mediated by IL-1, inflammatory pathway important early immunity during M. infection. IL-1 contribute pathology...
Tuberculosis (TB) is a major cause of morbidity and mortality worldwide despite widespread intradermal (ID) BCG vaccination in newborns. We previously demonstrated that changing the route dose from 5×10
ABSTRACT Coxiella burnetii is an intracellular bacterial pathogen that causes human Q fever, acute debilitating flu-like illness can also present as chronic endocarditis. Disease typically occurs following inhalation of contaminated aerosols, resulting in initial pulmonary infection. In cells, C. generates a replication niche termed the parasitophorous vacuole (PV) by directing fusion with autophagosomes and lysosomes. requires this lysosomal environment for uses Dot/Icm type IV secretion...
Coxiella burnetii is the causative agent of human Q fever, a debilitating flu-like illness that can progress to chronic disease presenting as endocarditis. Following inhalation, C. phagocytosed by alveolar macrophages and generates lysosome-like replication compartment termed parasitophorous vacuole (PV). A type IV secretion system (T4SS) required for PV generation one pathogen's few known virulence factors. We previously showed actively recruits autophagosomes using T4SS but does not alter...
Coxiella burnetii causes human Q fever, a zoonotic disease that presents with acute flu-like symptoms and can result in chronic life-threatening endocarditis. In alveolar macrophages, C. uses Dot/Icm type IV secretion system (T4SS) to generate phagolysosome-like parasitophorous vacuole (PV) which replicate. The T4SS translocates effector proteins, or substrates, into the host cytosol, where they mediate critical cellular events, including interaction autophagosomes, PV formation, prevention...
Abstract Mycobacterium tuberculosis lung infection results in a complex multicellular structure, the granuloma. In some granulomas, immune activity promotes bacterial clearance; others, bacteria persist and grow. We identified correlates of control cynomolgus macaque granulomas by co-registering longitudinal PET-CT imaging, single-cell RNA-sequencing, measures clearance. find that persistence occurs enriched for mast, endothelial, fibroblast plasma cells, signaling amongst themselves via...
Coxiella burnetii is an intracellular bacterial pathogen that causes human Q fever, acute flu-like illness can progress to chronic endocarditis and liver bone infections. Humans are typically infected by aerosol-mediated transmission, C. initially targets alveolar macrophages wherein the replicates in a phagolysosome-like niche known as parasitophorous vacuole (PV). manipulates host cAMP-dependent protein kinase (PKA) signaling promote PV formation, cell survival, replication. In this study,...
Abstract Intravenous (IV) BCG delivery provides robust protection against Mycobacterium tuberculosis (Mtb) in macaques but poses safety challenges. Here, we constructed two strains (BCG-TetON-DL and BCG-TetOFF-DL) which tetracyclines regulate phage lysin operons. Once the lysins are expressed, these killed immunocompetent immunocompromised mice yet induced similar immune responses provided Mtb challenge as wild type BCG. Lysin induction resulted release of intracellular antigens enhanced...
Abstract In 2017 over 550,000 estimated new cases of multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) occurred, emphasizing a need for treatment strategies. Linezolid (LZD) is potent antibiotic drug-resistant Gram-positive infections and an effective TB. However, extended LZD use can lead to LZD-associated host toxicities, most commonly bone marrow suppression. toxicities may be mediated by IL-1, inflammatory pathway important early immunity during M. infection. IL-1 contribute...
Abstract Background We previously demonstrated in non-human primates (NHP) that intravenous (IV) administration of BCG induces substantial T cell responses and often sterilizing immunity against Mycobacterium tuberculosis (Mtb) infection. Here, we investigated the role populations this unmatched response context necessary immune mechanisms for protection (TB). Methods Beginning 20 weeks after vaccination through end study, rhesus macaques were infused with antibodies to deplete CD4, CD8α, or...
Abstract Coxiella burnetii is the causative agent of human Q fever, a debilitating flu like illness that can progress to chronic disease presenting as endocarditis. After inhalation, C. phagocytosed by alveolar macrophages and generates lysosome-like replication niche known parasitophorous vacuole (PV). A type IV secretion system (T4SS) required for generation PV one pathogen’s few virulence factors. We previously showed actively recruits autophagosomes using T4SS, but does not alter...
Abstract Q fever is an emerging zoonosis caused by the intracellular bacterium, Coxiella burnetii. Disease can present as acute illness with debilitating flu-like symptoms or a chronic resulting in life-threatening endocarditis. Alveolar macrophages are primary target cell for infection which C. burnetii traffics through phagolysosomal pathway. Upon fusion lysosomes, uses type IV secretion system (T4SS) to modify and expand this compartment into replication niche termed parasitophorous...