Biology subjects

Maselli, D. J.

Publications and source records attributed to Maselli, D. J..

3 recordsLinked to original sources

bioRxiv2021

A Marmoset Model for Mycobacterium avium Complex Pulmonary Disease

RationaleMycobacterium avium complex, is the most common nontuberculous mycobacterial respiratory pathogen in humans. Disease mechanisms are poorly understood due to the absence of a reliable animal model for M. avium complex pulmonary disease. ObjectiveAssess the susceptibility, immunologic and histopathologic responses of the common marmoset (Callithrix jacchus) to M. avium complex pulmonary infection. Methods7 adult female marmosets underwent endobronchial inoculation with 108 colony-forming units of M. intracellulare and were monitored for 30 or 60 days. Prior to infection, chest radiograph and serum cytokines were assessed; serum cytokines were also monitored weekly for 30 days. At sacrifice 30 days (3 animals) or 60 days (4 animals) after infection, chest radiograph, serum and bronchoalveolar lavage cytokines, histopathology, and cultures of the bronchoalveolar lavage, lungs, liver, and kidney were analyzed. Measurements and Main ResultsFive of seven animals (two at 30 days and three at 60 days of infection) had positive lung cultures for M. intracellulare. Extra-pulmonary cultures were positive in three animals. All animals appeared healthy throughout the study. All five animals with positive lung cultures had radiographic changes consistent with pneumonitis. At 30 days, those with M. intracellulare lung infection showed granulomatous inflammation while at 60 days there was less inflammatory change, but bronchiectasis was noted. The cytokine response in the bronchoalveolar lavage fluid was uniformly greater in the animals with positive M. intracellulare cultures than those without a productive infection with greater levels at 30-days compared to 60-days. Similarly, serum cytokines were more elevated in the animals that had positive M. intracellulare cultures compared to those without a productive infection, peaking 14-21 days after inoculation. ConclusionEndobronchial instillation of M. intracellulare resulted in pulmonary mycobacterial infection in marmosets with a differential immune response, radiographic and histopathologic abnormalities, and an indolent course consistent with M. avium complex lung infection in humans.

microbiology↗

bioRxiv2021

Host- and age-dependent transcriptional changes in Mycobacterium tuberculosis cell envelope biosynthesis genes after exposure to human alveolar lining fluid

Tuberculosis (TB) infection, caused by the airborne pathogen Mycobacterium tuberculosis (M.tb), resulted in almost 1.4 million deaths in 2019 and the number of deaths is predicted to increase by 20% over the next 5 years due to the COVID-19 pandemic. Upon reaching the alveolar space, M.tb comes in close contact with the lung mucosa before and after its encounter with host alveolar compartment cells. Our previous studies show that homeostatic innate soluble components of the alveolar lining fluid (ALF) can quickly alter the cell envelope surface of M.tb upon contact, defining subsequent M.tb-host cell interactions and infection outcomes in vitro and in vivo. We also demonstrated that ALF from 60+ year old elders (E-ALF) vs. healthy 18- to 45-year-old adults (A-ALF) is dysfunctional with loss of homeostatic capacity and impaired innate soluble responses linked to high local oxidative stress. In this study, a targeted transcriptional assay demonstrates that M.tb exposure to human ALF alters the expression of its cell envelope genes. Specifically, our results indicate that A-ALF-exposed M.tb upregulates cell envelope genes associated with lipid, carbohydrate, and amino acid metabolism, as well as genes associated with redox homeostasis and transcriptional regulators. Conversely, M.tb exposure to E-ALF shows lesser transcriptional response, with most of the M.tb genes unchanged or downregulated. Overall, this study indicates that M.tb responds and adapts to the lung alveolar environment upon contact, and that the host ALF status determined by factors such as age might play an important role in determining infection outcome.

molecular biology↗

bioRxiv2021

Human alveolar lining fluid from the elderly promotes Mycobacterium tuberculosis growth in alveolar epithelial cells and bacterial translocation into the cytosol

The elderly population is at significant risk of developing respiratory diseases, including tuberculosis (TB) caused by the airborne Mycobacterium tuberculosis (M.tb). Once M.tb reaches the alveolar space, it contacts alveolar lining fluid (ALF) which dictates host cell interactions. We previously determined that age-associated dysfunctionality in human ALF soluble innate components lead to accelerated M.tb growth within human alveolar macrophages. Here we determined the impact of human ALF on M.tb infection of alveolar epithelial cells (ATs), another critical cellular determinant of infection. We observed that E-ALF-exposed M.tb had significantly increased intracellular growth in ATs compared to adult ALF (A-ALF)-exposed bacteria. Despite this, there were no alterations in AT inflammatory mediators or cell activation. However, exposure to E-ALF altered endosomal trafficking of M.tb, driving bacterial translocation to both endosomal and cytosolic compartments in ATs. Our results indicate that exposure of M.tb to E-ALF promotes translocation of bacteria into the AT cytosol as a potential favorable niche for rapid bacterial growth and at the same time dampens ATs immune responses. Thus, our findings highlight the influence of the elderly lung mucosa on M.tb infection of ATs, an unexplored contributing factor to the elderly populations increased susceptibility of developing active TB disease.

immunology↗