Concomitant Immunity Induced by Persistent Leishmania major Does Not Preclude Secondary Re-Infection: Implications for Genetic Exchange, Diversity and Vaccination

Mandell, Michael A.; Beverley, Stephen M.

doi:10.1371/journal.pntd.0004811

Cited by 15 publications

(11 citation statements)

References 71 publications

(106 reference statements)

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“…Although we have not evaluated the parasitic load in the draining lymph nodes, it is known that even in cured animals the persistence of parasites in the draining lymph node occurs for long periods. The persistence of parasites seems to be important for the maintenance of the cellular immune response and generation of T cell memory (Mandell and Beverley, 2016; Conceição-Silva et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Immunomodulation From Moderate Exercise Promotes Control of Experimental Cutaneous Leishmaniasis

Terra

Alves

Lima

et al. 2019

Front. Cell. Infect. Microbiol.

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Physical exercise has been described as an important tool in the prevention and treatment of numerous diseases as it promotes a range of responses and adaptations in several biological systems, including the immune system. Studies on the effect of exercise on the immune system could play a critical role in improving public health. Current literature suggests that moderate intensity exercise can modulate the Th1/Th2 dichotomy directing the immune system to a Th1 cellular immune response, which favors the resolution of infections caused by intracellular microorganisms. Leishmaniasis is a group of diseases presenting a wide spectrum of clinical manifestations that range from self-limiting lesions to visceral injuries whose severity can lead to death. The etiological agents responsible for this group of diseases are protozoa of the genus Leishmania. Infections by the parasite Leishmania major in mice (Balb/c) provide a prototype model for the polarization of CD4+ T cell responses of both Th1 (resistance) or Th2 (susceptibility), which determines the progression of infections. The aim of this study was to evaluate the effect of exercise on the development of L. major experimental infections by scanning the pattern of immune response caused by exercise. Groups of Balb/c mice infected with L. major were divided into groups that preformed a physical exercise of swimming three times a week or were sedentary along with treatment or not with the reference drug, meglumine antimoniate. Animals in groups submitted to physical exercise did not appear to develop lesions and presented a significantly lower parasite load independent of drug treatment. They also showed a positive delayed hypersensitivity response to a specific Leishmania antigen compared to control animals. The IFN-γ/IL-4 and IFN-γ/IL10 ratios in trained animals were clearly tilted to a Th1 response in lymph node cells. These data suggest that moderate intensity exercise is able to modulate the Th1 response that provides a protective effect against the development of leishmanial lesions.

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Section: Discussionmentioning

confidence: 99%

Immunomodulation From Moderate Exercise Promotes Control of Experimental Cutaneous Leishmaniasis

Terra

Alves

Lima

et al. 2019

Front. Cell. Infect. Microbiol.

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“… Stenger et al (1996) showed the reactivation of latent leishmaniasis by inhibition of inducible nitric oxide synthase in mice experimentally infected with L. major . However, recently two populations: one rapidly replicating, like parasites in acute infections, and another showing little evidence of replication were demonstrated in the persistent infection by L. major ( Mandell and Beverley, 2016 , 2017 ). The persistent parasite were found residing in macrophages and DCs expressing inducible nitric oxide synthase (iNOS), instead of “safe” immunoprivileged cell types, suggesting that some populations of Leishmania may be resistant to NO ( Mandell and Beverley, 2017 ).…”

Section: Parasite Persistencementioning

confidence: 99%

The Binomial Parasite-Host Immunity in the Healing Process and in Reactivation of Human Tegumentary Leishmaniasis

2018

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Leishmaniasis is a vector-borne infectious disease caused by different species of protozoa from the Leishmania genus. Classically, the disease can be classified into two main clinical forms: Visceral (VL) and Tegumentary (TL) leishmaniasis. TL is a skin/mucosal granulomatous disease that manifests mainly as cutaneous localized or disseminated ulcers, papules diffusely distributed, mucosal lesions or atypical lesions. Once the etiology of the infection is confirmed, treatment can take place, and different drugs can be administered. It has already been shown that, even when the scar is clinically evident, inflammation is still present in the native tissue, and the decrease of the inflammatory process occurs slowly during the 1st years after clinical healing. The maintenance of residual parasites in the scar tissue is also well documented. Therefore, it is no longer a surprise that, under some circumstances, therapeutic failure and/or lesion reactivation occurs. All over the years, an impressive amount of data on relapses, treatment resistance and lesion reactivation after healing has been collected, and several factors have been pointed out as having a role in the process. Different factors such as Leishmania species, parasite variability, Leishmania RNA virus 1, parasite load, parasite persistence, age, nutritional status, gender, co-morbidities, co-infection, pregnancy, immunosuppression, lesion duration, number and localization of lesions, drug metabolism, irregular treatment and individual host cellular immune response were described and discussed in the present review. Unfortunately, despite this amount of information, a conclusive understanding remains under construction. In addition, multifactorial influence cannot be discarded. In this context, knowing why leishmaniasis has been difficult to treat and control can help the development of new approaches, such as drugs and immunotherapy in order to improve healing maintenance. In this sense, we would like to highlight some of the findings that may influence the course of Leishmania infection and the therapeutic response, with an emphasis on TL.

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“…Second, they pose a substantial risk to infected people in the event of immunosuppression, as the persistent parasites can "reactivate," leading to severe disease (17). Finally, they maintain protective immunity to subsequent Leishmania infections through concomitant immunity, which results in amelioration of disease pathology without sterilization of either the persistent or incoming parasite (18,19). Indeed, healed Leishmania infections are the gold standard in anti-Leishmania immunity, and to date no other vaccination approaches have proven as successful in humans (18).…”

mentioning

confidence: 99%

Continual renewal and replication of persistentLeishmania majorparasites in concomitantly immune hosts

Mandell

Beverley

2017

Proc. Natl. Acad. Sci. U.S.A.

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112

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In most natural infections or after recovery, small numbers of Leishmania parasites remain indefinitely in the host. Persistent parasites play a vital role in protective immunity against disease pathology upon reinfection through the process of concomitant immunity, as well as in transmission and reactivation, yet are poorly understood. A key question is whether persistent parasites undergo replication, and we devised several approaches to probe the small numbers in persistent infections. We find two populations of persistent Leishmania major: one rapidly replicating, similar to parasites in acute infections, and another showing little evidence of replication. Persistent Leishmania were not found in "safe" immunoprivileged cell types, instead residing in macrophages and DCs, ∼60% of which expressed inducible nitric oxide synthase (iNOS). Remarkably, parasites within iNOS + cells showed normal morphology and genome integrity and labeled comparably with BrdU to parasites within iNOS − cells, suggesting that these parasites may be unexpectedly resistant to NO. Nonetheless, because persistent parasite numbers remain roughly constant over time, their replication implies that ongoing destruction likewise occurs. Similar results were obtained with the attenuated lpg2 − mutant, a convenient model that rapidly enters a persistent state without inducing pathology due to loss of the Golgi GDP mannose transporter. These data shed light on Leishmania persistence and concomitant immunity, suggesting a model wherein a parasite reservoir repopulates itself indefinitely, whereas some progeny are terminated in antigen-presenting cells, thereby stimulating immunity. This model may be relevant to understanding immunity to other persistent pathogen infections.latency | quiescence | trypanosomatid protozoan parasite | vaccination | stem cell-like

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Concomitant Immunity Induced by Persistent Leishmania major Does Not Preclude Secondary Re-Infection: Implications for Genetic Exchange, Diversity and Vaccination

Cited by 15 publications

References 71 publications

Immunomodulation From Moderate Exercise Promotes Control of Experimental Cutaneous Leishmaniasis

Immunomodulation From Moderate Exercise Promotes Control of Experimental Cutaneous Leishmaniasis

The Binomial Parasite-Host Immunity in the Healing Process and in Reactivation of Human Tegumentary Leishmaniasis

Continual renewal and replication of persistentLeishmania majorparasites in concomitantly immune hosts

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