Microbial Translocation Induces an Intense Proinflammatory Response in Patients With Visceral Leishmaniasis and HIV Type 1 Coinfection

Santos-Oliveira, Joanna Reis; Regis, Eduardo G.; Giacoia-Gripp, Carmem Beatriz Wagner; Valverde, Joanna Gardel; Alexandrino-de-Oliveira, Priscilla; Lindoso, José Ângelo Lauletta; Goto, Hiro; Oliveira-Neto, Manoel P.; Guerra, Jorge Augusto de Oliveira; Grinsztejn, Beatriz; Jerônimo, Selma M. B.; Morgado, Mariza G.; Da‐Cruz, Alda Maria

doi:10.1093/infdis/jit135

Cited by 40 publications

(48 citation statements)

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“…Of note, we found high levels of microbial translocation in VL patients, in accordance with the findings of previous noncomparative studies that also showed high levels of proinflammatory response and high levels of LPS in patients with VL [35]. Thus, these data suggest a greater deterioration of the mucosal tissue in patients with Leishmania infection [11] than that observed in other HIV-1-infected patients.…”

Section: Discussionsupporting

confidence: 92%

Visceral leishmaniasis as an independent cause of high immune activation, T‐cell senescence, and lack of immune recovery in virologically suppressed HIV‐1‐coinfected patients

Casado¹,

Abad-Fernández²,

Moreno³

et al. 2015

HIV Medicine

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ObjectivesDifferent immune alterations have been described in HIV-infected patients with visceral leishmaniasis (VL). We aimed to identify the immunological factors involved in the lack of immunological recovery and VL relapses in HIV-infected patients with VL, by comparison with other HIV-infected patients. MethodsWe carried out a cross-sectional study of 55 patients receiving suppressive combination antiretroviral therapy (cART) for at least 1 year: nine with previous relapsing VL, 20 with an immunodiscordant response (IDR) to cART (CD4 count < 200 cells/μL) and no previous VL, and 26 with a concordant response (CR) to cART (CD4 count > 350 cells/μL) without VL. Immunosenescence was investigated by analysing CD57 + CD28− levels, immune activation by analysing CD38 + HLA-DR + levels, inflammation by analysing interleukin (IL)-6 levels, and microbial translocation by analysing lipopolysaccharide (LPS) and soluble CD14 (sCD14) levels. ResultsIn VL patients, the median time since VL diagnosis was 42 months, and all patients had had at least one relapse despite suppressive cART for a median time of 43 months. Patients with previously diagnosed VL had a higher CD8 T-cell activation level (P < 0.001) than those with IDR. Also, levels of IL-6, LPS and especially sCD14, associated with bacterial translocation and additional monocyte activation, were significantly increased in patients with previous VL compared with patients with IDR (P = 0.048, P = 0.049 and P < 0.001, respectively). In addition, patients with previous VL had higher levels of CD8 T-cell senescence. Notably, the levels of immune activation and inflammation in patients with previous VL were not related to the time of VL diagnosis, the number of VL relapses, or hepatitis C virus (HCV) coinfection. ConclusionsOur data demonstrate that VL patients had an even worse immunological status than patients with IDR, which was probably associated with increased microbial translocation and additional monocyte/macrophage activation. These data explain the observed lack of immunological recovery and the occurrence of VL relapses in HIV-infected patients with previous VL. Specifically, visceral leishmaniasis (VL) is an infectious disease caused mainly by Leishmania donovani and Leishmania infantum (Leishmania chagasi), intracellular protozoans that infect macrophage cell lineages from lymphoid organs. It is a common coinfection in HIV-1-infected individuals in the Mediterranean basin, including Spain, with a prevalence of up to 9%. VL/HIV-1 coinfection is characterized by significantly lower cure rates, higher drug toxicity, higher relapse rates, and higher mortality rates (nearly 50%) than those for non-HIV-1-infected individuals with VL [5,6].While cART has been shown to decrease the incidence of leishmaniasis in HIV-1-infected patients, it does not seem to prevent the appearance of frequent relapses in patients previously diagnosed and largely pretreated with antiretrovirals [7][8][9], demonstrating the persistence of the parasite in different cell lines. Moreover, ...

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Section: Discussionsupporting

confidence: 92%

Visceral leishmaniasis as an independent cause of high immune activation, T‐cell senescence, and lack of immune recovery in virologically suppressed HIV‐1‐coinfected patients

Casado¹,

Abad-Fernández²,

Moreno³

et al. 2015

HIV Medicine

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“…A similar phenomenon was described in VL, most likely as a consequence of intestinal infection by Leishmania [29], [49]–[52]. The consequent translocation of bacterial components, such as lipopolysaccharides (LPS), may contribute to an enhancement of cellular activation by stimulating the innate and adaptive immune systems [53], creating an inflammatory environment that results in the increased proliferation and activation of T cells and causing a loss in systemic immune function [54], [55].…”

Section: Immunopathogenesismentioning

confidence: 74%

“…Those features can explain the elevated parasite load observed in bone marrow samples [27], [28] and peripheral blood [28], [29].…”

Section: Immunopathogenesismentioning

confidence: 93%

“…Moreover, a proinflammatory cytokine storm may occur in VL in which IFN-γ, tumor necrosis factor (TNF), interleukin (IL)-1β, IL-6, IL-8, IL-17, macrophage inflammatory protein (MIP)-1β, and macrophage migration inhibitory factor (MIF) are released [29], [43]–[45]. Consistently, increased percentages of molecules associated with T cell activation, such as CD38 on CD8 + T cells and HLA-DR, are observed in VL/HIV patients compared to HIV/AIDS cases alone, and these molecules do not reach normal values despite undetectable viral load and clinical remission of leishmaniasis [46].…”

Section: Immunopathogenesismentioning

confidence: 99%

“…Then, the involvement of microbial products in addition to the Leishmania parasite itself could account for the immunopathogenesis of VL/HIV patients. As a consequence, secondary chemoprophylaxis for leishmaniasis or even the use of anti-inflammatory drugs or strategies to reestablish the normal gut flora can be considered to improve the prognosis of VL/HIV [29], [56].…”

Section: Immunopathogenesismentioning

confidence: 99%

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Visceral Leishmaniasis and HIV Coinfection in Latin America

et al. 2014

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Visceral leishmaniasis (VL) is an endemic zoonotic disease in Latin America caused by Leishmania (Leishmania) infantum, which is transmitted by sand flies from the genus Lutzomyia. VL occurs in 12 countries of Latin America, with 96% of cases reported in Brazil. Recently, an increase in VL, primarily affecting children and young adults, has been observed in urban areas of Latin America. The area in which this spread of VL is occurring overlaps regions with individuals living with HIV, the number of whom is estimated to be 1.4 million people by the World Health Organization. This overlap is suggested to be a leading cause of the increased number of reported VL-HIV coinfections. The clinical progression of HIV and L. infantum infections are both highly dependent on the specific immune response of an individual. Furthermore, the impact on the immune system caused by either pathogen and by VL-HIV coinfection can contribute to an accelerated progression of the diseases. Clinical presentation of VL in HIV positive patients is similar to patients without HIV, with symptoms characterized by fever, splenomegaly, and hepatomegaly, but diarrhea appears to be more common in coinfected patients. In addition, VL relapses are higher in coinfected patients, affecting 10% to 56.5% of cases and with a lethality ranging from 8.7% to 23.5% in Latin America, depending on the study. With regards to the diagnosis of VL, parasitological tests of bone marrow aspirates have proven to be the most sensitive test in HIV-infected patients. Serologic tests have demonstrated a variable sensitivity according to the method and antigens used, with the standard tests used for diagnosing VL in Latin America displaying lower sensitivity. For this review, few articles were identified that related to VL-HIV coinfections and originated from Latin America, highlighting the need for improving research within the regions most greatly affected. We strongly support the formation of a Latin American network for coinfections of Leishmania and HIV to improve the consistency of research on the current situation of VL-HIV coinfections. Such a network would improve the collection of vital data and samples for better understanding of the clinical manifestations and immunopathogenic aspects of VL in immunosuppressed patients. Ultimately, a concerted effort would improve trials for new diagnostic methodologies and therapeutics, which could accelerate the implementation of more specific and effective diagnosis as well as public policies for treatments to reduce the impact of VL-HIV coinfections on the Latin American population.

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Culture-Independent Omics-Techniques for Microbiome-Based Molecular Therapeutics Against Infectious Diseases

Sasidharan

Divakar²,

Saudagar

2020

Metagenomic Systems Biology

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Microbial Translocation Induces an Intense Proinflammatory Response in Patients With Visceral Leishmaniasis and HIV Type 1 Coinfection

Cited by 40 publications

References 41 publications

Visceral leishmaniasis as an independent cause of high immune activation, T‐cell senescence, and lack of immune recovery in virologically suppressed HIV‐1‐coinfected patients

Visceral leishmaniasis as an independent cause of high immune activation, T‐cell senescence, and lack of immune recovery in virologically suppressed HIV‐1‐coinfected patients

Visceral Leishmaniasis and HIV Coinfection in Latin America

Culture-Independent Omics-Techniques for Microbiome-Based Molecular Therapeutics Against Infectious Diseases

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