IL-10 underlies distinct susceptibility of BALB/c and C57BL/6 mice to Mycobacterium avium infection and influences efficacy of antibiotic therapy

Increased production of IL-10 has been frequently associated with augmented susceptibility to infection. However, the correlation between IL-10 activity and susceptibility to mycobacterial infection is still uncertain. Although studies using transgenic mice overexpressing IL-10 consistently showed an increased susceptibility to mycobacterial infection, experimental approaches in which IL-10 activity was reduced or abrogated originated inconclusive data. We show here that this controversy might be due to the mouse strains used in the various experimental procedures. Our results show that BALB/c mice are more susceptible than C57BL/6 to Mycobacterium avium infection. This increased susceptibility of BALB/c mice is, to a great extent, due to distinct activity of IL-10 between the two mouse strains. In accordance, reduction of IL-10 activity through the administration of anti-IL-10R mAb, or the absence of IL-10 as studied in IL-10 knockout mice, clearly decreased the susceptibility of BALB/c mice to M. avium but had a less obvious effect in C57BL/6 mice. Moreover, abrogation of IL-10 activity in infected BALB/c mice increased the efficacy of antimycobacterial therapy, whereas for the C57BL/6 mice it produced no effect. These observations show that the activity of IL-10 in response to the same mycobacterial stimulus influences not only the susceptibility to infection but also the efficacy of antimycobacterial therapy. This should now be considered in the context of human response to mycobacterial infection, particularly as a possible strategy to improve treatment against infections by mycobacteria

Increased susceptibility to Mycobacterium avium in hemochromatosis protein HFE-deficient mice

Mycobacterium avium is an opportunistic infectious agent in immunocompromised patients, living inside macrophage phagosomes. As for other mycobacterial species, iron availability is a critical factor for M. avium survival and multiplication. Indeed, an association between host secondary iron overload and increased susceptibility to these mycobacteria is generally acknowledged. However, studies on the impact of primary iron overload on M. avium infection have not been performed. In this work, we used animal models of primary iron overload that mimic the human disease hereditary hemochromatosis. This pathology is characterized by increased serum transferrin saturation with iron deposition in parenchymal cells, mainly in the liver, and is most often associated with mutations in the gene encoding the molecule HFE. In this paper, we demonstrate that mice of two genetically determined primary iron overload phenotypes, Hfe(-/-) and beta 2m(-/-), show an increased susceptibility to experimental infection with M. avium and that during infection these animals accumulate iron inside granuloma macrophages. beta 2m(-/-) mice were found to be more susceptible than Hfe(-/-) mice, but depleting Hfe(-/-) mice of CD8(+) cells had no effect on resistance to infection. Overall, our results suggest that serum iron, rather than total liver iron, levels have a considerable impact on susceptibility to M. avium infection

Biomedical applications of human cathelicidin

[Excerpt] Antimicrobial peptides (AMPs) are good candidates to treat burn wounds, a major cause of morbidity, impaired life quality and resources consumption in developed countries. Tuberculosis (TB), a disease caused by the human pathogen Mycobacterium tuberculosis, represents the second world’s deadliest infectious disease, affecting around 9 million people worldwide in 2013. Of those, about 1.1 million died from the disease. The potential of cathelicin, a human AMP, in the treatment of mycobacteriosis and wound regeneration was assessed in pre-clinical trials. (...

Delivery of antimicrobial peptides for the treatment of mycobacteriosis

Mycobacterium tuberculosis, which resides inside macrophages, has always been recognized as one of the most “successful” pathogens. Standard treatments have already been used for decades and, therefore, resistances to the first-line medicines are increasing. Additionally, poor patient compliance with stringent therapies is often pointed out as a major reason leading to treatment failure. Antimicrobial peptides (AMPs), a promising new class of broad spectrum antibiotics, are less prone to result in pathogen resistances due to their target (cellular membranes) and rapid action. In our laboratory we search for AMPs with potent activity against mycobacteria and try to develop efficient delivery systems based on self-assembled colloidal nanocarriers. Additionally, this systems are expected to reduce peptide toxicity and enhance selective uptake on infected cells. Finally, the use of encapsulated drugs in mycobacterial therapy may help reducing drug administration schedules which would ultimately improve patient compliance

The effect of the host's iron status on tuberculosis

Several lines of evidence have suggested that iron is critical for Mycobacterium tuberculosis growth in macrophages. Macrophage iron loading in patients with African iron overload increases the risk of tuberculosis (TB) and may worsen TB outcome. Likewise, macrophage iron loading may contribute to an increased predisposition toward TB in HIV infection. Human genetic disorders or variations may increase the risk of TB or worsen its outcome through macrophage iron loading, including the haptoglobin 2-2 phenotype, NRAMP1 polymorphisms (at least in Africans and Asians), and possibly ferroportin 1 mutations, but not HFE hemochromatosis. Thus, the host\u27s iron status may be an important yet underevaluated factor in TB prevention and therapy and in TB vaccine design. © 2007 by the Infectious Diseases Society of America. All rights reserved

Delivery of nanogel formulations with antimicrobial peptides for the treatment of mycobacteriosis

Book of Abstracts of CEB Annual Meeting 2017[Excerpt] Mycobacterium tuberculosis is the human pathogen that causes Tuberculosis (TB). In 2015, 10.4 million TB cases and 1.8 million deaths were reported, placing this disease alongside HIV/AIDS as the deadliest infectious diseases. Current treatments rely in the administration of a cocktail of four first-line antibiotics during 6 months and, in the worst case scenario, a long-lasting treatment (24 months) with second-line drugs. The overuse or misuse of antimicrobial agents decreases the success of treatments and increases emergence of Multi-drug resistant (MDR) strains. Therefore, the development of new strategies for TB therapy is urgently needed. In this scope, antimicrobial peptides (AMPs) arise as promising candidates for TB treatment since they present high spectrum of antimicrobial activity, high efficacy at low concentrations and low propensity for bacterial resistance. Nevertheless, the low capacity of AMPs to reach the infected site and the use of high concentrations to overcome this problem limits its clinical application - this can be circumvented using a drug delivery system [1]. [...]info:eu-repo/semantics/publishedVersio

Dissemination of mycobacteria to the thymus renders newly generated T cells tolerant to the invading pathogen

The ability of the thymus to generate a population of T cells that is, for the most part, self-restricted and self-tolerant depends to a great extent on the Ags encountered during differentiation. We recently showed that mycobacteria disseminate to the thymus, which raised the questions of how mycobacteria within the thymus influence T cell differentiation and whether such an effect impacts host-pathogen interactions. Athymic nude mice were reconstituted with thymic grafts from Mycobacterium avium-infected or control noninfected donors. T cells generated from thymi of infected donors seemed generally normal, because they retained the ability to reconstitute the periphery and to respond to unspecific stimuli in vitro as well as to antigenic stimulation with third-party Ags, such as OVA, upon in vivo immunization. However, these cells were unable to mount a protective immune response against a challenge with M. avium. The observation that thymic infection interferes with T cell differentiation, generating T cells that are tolerant to pathogen-specific Ags, is of relevance to understand the immune response during chronic persistent infections. In addition, it has potential implications for the repertoire of T cells generated in patients with a mycobacterial infection recovering from severe lymphopenia, such as patients coinfected with HIV and receiving antiretroviral therapy.Fundação para a Ciência e Tecnologia and Fundo Europeu de Desenvolvimento Regional (PIC/IC/83313/2007; PTDC/SAU-MII/101663/2008) and the American-Portuguese Biomedical Research Fund. C.N., S.R., and C.N.-A. are recipients of PhD fellowships from Fundação para a Ciência e Tecnologi

Iron Overload Favors the Elimination of Leishmania

Iron plays a central role in host-parasite interactions, since both intervenients need iron for survival and growth, but are sensitive to iron-mediated toxicity. The host’s iron overload is often associated with susceptibility to infection. However, it has been previously reported that iron overload prevented the growth of Leishmania major, an agent of cutaneous leishmaniasis, in BALB/c mice. In order to further clarify the impact of iron modulation on the growth of Leishmania in vivo, we studied the effects of iron supplementation or deprivation on the growth of L. infantum, the causative agent of Mediterranean visceral leishmaniasis, in the mouse model. We found that dietary iron deficiency did not affect the protozoan growth, whereas iron overload decreased its replication in the liver and spleen of a susceptible mouse strain. The fact that the iron-induced inhibitory effect could not be seen in mice deficient in NADPH dependent oxidase or nitric oxide synthase 2 suggests that iron eliminates L. infantum in vivo through the interaction with reactive oxygen and nitrogen species. Iron overload did not significantly alter the mouse adaptive immune response against L. infantum. Furthermore, the inhibitory action of iron towards L. infantum was also observed, in a dose dependent manner, in axenic cultures of promastigotes and amastigotes. Importantly, high iron concentrations were needed to achieve such effects. In conclusion, externally added iron synergizes with the host’s oxidative mechanisms of defense in eliminating L. infantum from mouse tissues. Additionally, the direct toxicity of iron against Leishmania suggests a potential use of this metal as a therapeutic tool or the further exploration of iron anti-parasitic mechanisms for the design of new drugs