Dynamics of immune effector mechanisms during infection with Mycobacterium avium in C57BL/6 mice

Abstract

SummaryOpportunistic infections with non-tuberculous mycobacteria such as Mycobacterium avium are receiving renewed attention because of increased incidence and difficulties in treatment. As for other mycobacterial infections, a still poorly understood collaboration of different immune effector mechanisms is required to confer protective immunity. Here we have characterized the interplay of innate and adaptive immune effector mechanisms contributing to containment in a mouse infection model using virulent M. avium strain 104 in C57BL/6 mice. M. avium caused chronic infection in mice, as shown by sustained organ bacterial load. In the liver, bacteria were contained in granuloma-like structures that could be defined morphologically by expression of the antibacterial innate effector protein Lipocalin 2 in the adjoining hepatocytes and infiltrating neutrophils, possibly contributing to containment. Circulatory antimycobacterial antibodies steadily increased throughout infection and were primarily of the IgM isotype. Highest levels of interferon-c were found in infected liver, spleen and serum of mice approximately 2 weeks post infection and coincided with a halt in organ bacterial growth. In contrast, expression of tumour necrosis factor was surprisingly low in spleen compared with liver. We did not detect interleukin-17 in infected organs or M. avium-specific T helper 17 cells, suggesting a minor role for T helper 17 cells in this model. A transient and relative decrease in regulatory T cell numbers was seen in spleens. This detailed characterization of M. avium infection in C57BL/6 mice may provide a basis for future studies aimed at gaining better insight into mechanisms leading to containment of infections with non-tuberculous mycobacteria.

Prominent contribution of Th1, Th17, and Tregs to the host response during M. neoaurum infection

“…Although we observed a general increase in mRNA expression of Foxp3 in the lungs, this did not translate into a difference in overall Treg cell numbers at 56 days post infection. However, the number of Tregs in the lungs and spleen (not shown) decreased between 7 and 21 days after infection, which is in agreement with a previous study on M. avium infection (Haug et al, 2013). This phase may favor immune activation and inflammation rather than suppression, which may help contain the infection.…”

Susceptibility of Mycobacterium abscessus to Antimycobacterial Drugs in Preclinical Models

“…The immune systems of the following mice were capable of clearing M. abscessus: the beige mice with a dominant Th2 immunity; the Nos2 Ϫ/Ϫ mice lacking NO2; Cybb Ϫ/Ϫ mice, which are devoid of the superoxide-generating enzyme that forms the reactive oxygen species (ROS) associated with chronic granulomatous disease; TNFR Ϫ/Ϫ mice, which lack the tumor necrosis factor receptor; C3HeB/FeJ mice capable of forming tubercular granulomas and GKO Ϫ/Ϫ deficient in IFN-␥; and the MyD88 knockout mice, with an allele that encodes a deletion of exon 3 of the myeloid differentiation primary response deleteriously impacting innate and acquired immunity causing increased susceptibility to bacterial pathogens (19)(20)(21)(22)(23). After 40 days of infection, the C3HeB/FeJ, GKO Ϫ/Ϫ , and MyD88 Ϫ/Ϫ mice had bacterial loads of about 2.0 to 2.5 log 10 persisting in the lungs.…”

“…Additionally, Cybb knockout mice, a mouse model of chronic granulomatous disease (CGD), have a recessive disorder characterized by a defective phagocyte respiratory burst oxidase required for mycobacterial intracellular killing, but the lack of this oxidase does not allow for RGM survival (20). Moreover, targeting more essential genes for the cytokines required for clearance of M. tuberculosis and even Mycobacterium avium, such as the tumor necrosis factor receptor (TNFR) and IFN-␥, two cytokines essential for acquired immune removal of more virulent pathogens when knocked out, allowed for early RGM persistence but eventually resulted in clearance (21). The beige model has a dominant Th2 immunity that allows for M. avium growth (22); however, RGM are also removed by this model.…”

Lipocalin 2 Imparts Selective Pressure on Bacterial Growth in the Bladder and Is Elevated in Women with Urinary Tract Infection

“…However, the cellular source of LCN2 in the various conditions is unclear as LCN2 can be secreted from blood or tissue-infiltrating neutrophils, liver hepatocytes, mucosal epithelial cells or resident cells of spleen and kidney (18, 20, 24, 32, 37, 45, 46). In our mouse study, LCN2 was increased in the urinary tract as early as 6 hours after inoculation.…”