H-Ferritin Produced by Myeloid Cells Is Released to the Circulation and Plays a Major Role in Liver Iron Distribution during Infection

During infections, the host redistributes iron in order to starve pathogens from this nutrient. Several proteins are involved in iron absorption, transport, and storage. Ferritin is the most important iron storage protein. It is composed of variable proportions of two peptides, the L- and H-ferritins (FTL and FTH). We previously showed that macrophages increase their expression of FTH1 when they are infected in vitro with Mycobacterium avium, without a significant increase in FTL. In this work, we investigated the role of macrophage FTH1 in M. avium infection in vivo. We found that mice deficient in FTH1 in myeloid cells are more resistant to M. avium infection, presenting lower bacterial loads and lower levels of proinflammatory cytokines than wild-type littermates, due to the lower levels of available iron in the tissues. Importantly, we also found that FTH1 produced by myeloid cells in response to infection may be found in circulation and that it plays a key role in iron redistribution. Specifically, in the absence of FTH1 in myeloid cells, increased expression of ferroportin is observed in liver granulomas and increased iron accumulation occurs in hepatocytes. These results highlight the importance of FTH1 expression in myeloid cells for iron redistribution during infection.

The Role of NRF2 in Mycobacterial Infection

The incidence of pulmonary nontuberculous mycobacterial (NTM) infection is increasing worldwide, and its clinical outcomes with current chemotherapies are unsatisfactory. The incidence of tuberculosis (TB) is still high in Africa, and the existence of drug-resistant tuberculosis is also an important issue for treatment. To discover and develop new efficacious anti-mycobacterial treatments, it is important to understand the host-defense mechanisms against mycobacterial infection. Nuclear erythroid 2 p45-related factor-2 (NRF2) is known to be a major regulator of various antioxidant response element (ARE)-driven cytoprotective gene expressions, and its protective role has been demonstrated in infections. However, there are not many papers or reviews regarding the role of NRF2 in mycobacterial infectious disease. Therefore, this review focuses on the role of NRF2 in the pathogenesis of Mycobacterium tuberculosis and Mycobacterium avium infection.

Disseminated Mycobacterium avium infection in a young woman with sickle cell disease and iatrogenic iron overload

A 29-year-old woman with known sickle cell disease (SCD) and iatrogenic iron overload presented to the emergency department with a recurrent pain crisis and fever. Blood cultures obtained at a recent prior admission for the same complaints grew M avium. Bone marrow biopsy revealed non-caseating granulomas, but stains for mycobacteria and fungi were negative. Disseminated non-tuberculous mycobacterial infections (NTMIs) occur almost exclusively in immunosuppressed patients. SCD is not considered a risk factor for the development of disseminated NTMIs, making diagnosis challenging in this population. However, a number of case reports describing disseminated NTMIs in patients with SCD have been published. This case adds to the current literature, suggesting SCD with iatrogenic iron overload is a possible risk factor for disseminated NTMIs. Potential mechanisms for this increased risk include 1) functional asplenia, 2) iatrogenic iron overload, 3) chronic indwelling central venous catheters, and 4) hydroxyurea use. Further investigation is required to describe the strength and mechanism of the relationship between SCD and disseminated NTMIs.

The Tumor Necrosis Factor Alpha and Interleukin 6 Auto-paracrine Signaling Loop Controls Mycobacterium avium Infection via Induction of IRF1/IRG1 in Human Primary Macrophages

The prevalence of lung diseases caused by nontuberculous mycobacteria, such as Mycobacterium avium , is increasing in countries where tuberculosis is not endemic, most likely because of an aging population that is immunocompromised from underlying disease or immunosuppressive therapy. Our study contributes to the understanding of mycobacterial survival and killing in human macrophages and, more broadly, to the impact of immunometabolism during infection.

Targeting emerging Mycobacterium avium infections: perspectives into pathways and antimicrobials for future interventions

Mycobacterium avium is an emerging opportunistic pathogen, globally. Infections caused by M. avium are laborious to treat and could result in drug resistance. This review discusses the importance of many factors including the cell wall in M. avium pathogenesis, since this unique structure modulates the pathogen’s ability to thrive in various hosts and environmental niches including conferring resistance to killing by antimicrobials. More research efforts in future are solicited to develop novel therapeutics targeting M. avium. The complete eradication of M. avium infection in immunocompromised individuals would need a deeper understanding of the source of infection, unique underlying mechanisms and its uncharacterized pathways. This could, perhaps in future, hold the key to target and treat M. avium more effectively.

Disseminated Mycobacterium simiae and Mycobacterium avium infection causing an immune reconstitution inflammatory syndrome in a female patient with HIV infection

This case study discusses the management of a disseminated Mycobacterium simiae and Mycobacterium avium infection causing an immune reconstitution inflammatory syndrome in a 52-year-old woman with HIV infection. Disseminated M. avium infections have extensively been described in HIV patients; however, reports of infections with M. simiae are rare. Treatment of M. simiae infections is challenging due to its high rates of natural drug resistances, and thus far, no standard treatment regimen exists.

Nrf2 Regulates Granuloma Formation and Macrophage Activation during Mycobacterium avium Infection via Mediating Nramp1 and HO-1 Expressions

ABSTRACT Nrf2 is a redox-sensitive transcription factor that is thought to be important in protection against intracellular pathogens. To determine the protective role of Nrf2 in the host defense against Mycobacterium avium complex (MAC), both wild-type and Nrf2-deficient mice were intranasally infected with MAC bacteria. Nrf2-deficient mice were highly susceptible to MAC bacteria compared with wild-type mice. There were no significant changes in the levels of oxidative stress and Th1 cytokine production between genotypes. Comprehensive transcriptome analysis showed that the expressions of Nramp1 and HO-1 were much lower in the infected lungs, and the expression of Nramp1 was especially lower in alveolar macrophages of Nrf2-deficient mice than of wild-type mice. Electron microscopy showed that many infected alveolar macrophages from Nrf2-deficient mice contained a large number of intracellular MAC bacteria with little formation of phagolysosomes, compared with those from wild-type mice. Treatment with sulforaphane, an activator of Nrf2, increased resistance to MAC with increased lung expression of Nramp1 and HO-1 in wild-type mice. These results indicate that Nramp1 and HO-1, regulated by Nrf2, are essential in defending against MAC infection due to the promotion of phagolysosome fusion and granuloma formation, respectively. Thus, Nrf2 is thought to be a critical determinant of host resistance to MAC infection. IMPORTANCE Nontuberculous mycobacteria (NTM) are an important cause of morbidity and mortality in pulmonary infections. Among them, Mycobacterium avium complex (MAC) is the most common cause of pulmonary NTM disease worldwide. It is thought that both environmental exposure and host susceptibility are required for the establishment of pulmonary MAC disease, because pulmonary MAC diseases are most commonly observed in slender, postmenopausal women without a clearly recognized immunodeficiency. However, host factors that regulate MAC susceptibility have not been elucidated until now. This study shows that Nrf2 is a critical regulator of host susceptibility to pulmonary MAC disease by promoting phagolysosome fusion and granuloma formation via activating Nramp1 and HO-1 genes, respectively. The Nrf2 system is activated in alveolar macrophages, the most important cells during MAC infection, as both the main reservoir of infection and bacillus-killing cells. Thus, augmentation of Nrf2 might be a useful therapeutic approach for protection against pulmonary MAC disease.

Preliminary Seroepidemiological Investigation Regarding Mycobacterium Avium Infection in Wild Boars and Foxes

The present study aimed at identifying Mycobacterium avium seroprevalence in wild boars (Sus scrofa) and red foxes (Vulpes vulpes) samples, from the Eastern region of Romania, by using an indirect ELISA assay. A total of 367 wild animal samples were collected from eight counties: 275 wild boars sera samples from Iasi (n=209), Botosani (n=11), Bacau (n=17), Galati (n=27) and Covasna (n=11) and 92 fox samples of thoracic fluid from Iasi (n=30), Suceava (n=20), Neamt (n=19), Vaslui (n=11) and Galati (n=12). Specific antibodies were not detected in wild boar serum samples tested. From the fox samples, one was positive (1.08%), originating from Galati County. Our results may be correlated with a reduced distribution of Mycobacterium avium subspecies in the environment and a low prevalence of infections caused by these bacteria in wild animals. The current assessment shows that foxes have a limited role in the epidemiology of nontuberculous mycobacterial infections.