Hannah Akuffo

Poor immunogenicity of BCG in helminth infected population is associated with increased in vitro TGF-β production

The only vaccine available against tuberculosis (TB), BCG, so effective in experimental animal models, has been under scrutiny for a long time owing to its variable efficacy against pulmonary tuberculosis in adults. In this study, we evaluated whether anti-helminthic therapy prior to BCG vaccination could increase the immunogenicity of BCG vaccination in helminth infected population. We recruited volunteers with evidence of prior mycobacterial infection and who were asymptomatic carriers of helminths. The subjects were randomized to receive either anti-helminthic drugs or placebo. Three months later, BCG vaccination was administered to volunteers. Mycobacterial antigen-specific cytokine responses were assessed 2 months after vaccination. The results show that peripheral blood mononuclear cells obtained from the placebo group were found to have a lower frequency of IFN-gamma (129 vs 191, p=0.03) and IL-12 (149 vs 243, p=0.013) producing cells per 2 x 10(5) PBMC (peripheral blood mononuclear cells) when stimulated in vitro with a mycobacterial antigen mixture (purified protein derivative (PPD)) compared to those from the dewormed group. On the other hand the placebo group had higher frequency of TGF-beta producing cells in response to PPD (152 vs 81.3, p=0.002) or the T cell mitogen concanavalin A (Con A) (210 vs 157, p=0.03). However, no detectable IL-4 or IL-5 producing cells were observed when cells were stimulated with PPD. Comparable numbers of both cytokine producing cells were induced in both groups upon stimulation with concanavalin A (IL-4 217 vs 191, p=0.08) and IL-5 (131 vs 103, p=0.14). The data presented here demonstrate that chronic worm infection reduces the immunogenicity of BCG in humans and this was associated with increased TGF-beta production but not with enhanced Th2 immune response.

Leishmania–HIV Interaction: Immunopathogenic Mechanisms

Both Leishmania and the human immunodeficiency virus (HIV) can infect and multiply in macrophages, and both can dysregulate the immune system. Recent studies indicate that Leishmania can induce the activation of HIV in latently infected monocytic and T cells. Moreover, HIV can enhance intracellular growth of Leishmania in macrophages. Here, Dawit Wolday and colleagues examine the mechanisms that might be involved in the immunopathogenesis of Leishmania- HIV co-infection.

Genetic variability within the species Leishmania aethiopica does not correlate with clinical variations of cutaneous leishmaniasis.

Leishmania aethiopica infections in man result in a spectrum of diseases from LCL to DCL. These clinical manifestations have been attributed to genetic differences within the host or the parasites. In this study two different PCR-based methods were used to elucidate genetic variation within the species L. aethiopica. Inter- and intra-specific variations were detected in the ITS of the ribosomal operon in different strains and species of Leishmania, using a PCR-RFLP approach, and by a PCR fingerprinting technique that used single non-specific primers to amplify polymorphic regions of the genomic DNA. Both methods revealed genetic heterogeneity among ten L. aethiopica isolates examined. Unrooted distance trees separated the ten strains into two different genetic groups. This subdivision was correlated to the geographical origin of the isolates rather than to the clinical manifestation of the disease.

Hiv viral load and response to antileishmanial chemotherapy in co-infected patients

OBJECTIVE To investigate whether clearance of Leishmania parasites from tissue aspirate smears in patients with HIV and visceral leishmaniasis (VL) co-infection treated with pentavalent antimonials is influenced by initial HIV viral load and to assess the effect of active VL on HIV viral load and replication in vivo. METHODS Leishmania parasites were identified in Giemsa-stained smears prepared from tissue aspirates. Parasite index was determined by quantifying Leishmania donovani bodies in smears. HIV-1 RNA was quantitated by using the nucleic acid sequence-based amplification technique with a limit of detection of 500 copies/ml. All patients were treated with pentavalent antimonials at 20 mg pentavalent antimony (Sb(V))/kg daily for a total of 28 days. None of the patients received specific anti-retroviral therapy. RESULTS Seventeen patients (73.9%) showed good initial response to anti-leishmanial treatment and the remaining six (26.1%) had very poor response. Among the good responders, 11 (64.7%) had no demonstrable Leishmania donovani bodies in post-therapy tissue aspirate smear preparations, and in the remaining six (35.3%) their parasite loads were reduced to very low levels. Patients with poor response had persistently high parasite index despite completion of anti-leishmanial chemotherapy. Poor responders had pre-treatment median HIV viral load that was >160-fold higher than responders to anti-leishmanial chemotherapy; [410000 copies/ml (quartile range, 33000-530000) and 2500 copies/ml (quartile range 500-297500), respectively]. Furthermore, compared with pre-treatment viral concentrations, patients with good response showed marked reduction in post-treatment viral load. In contrast, post-treatment HIV viral concentrations were markedly increased among patients with poor response to anti-leishmanial therapy. CONCLUSIONS The results suggest that pre-treatment HIV viral load influences response to anti-leishmanial chemotherapy and active VL is associated with increased viral replication in vivo, supporting the notion that dual infection plays an important role in the pathogenesis and disease progression of either infection.

Are intestinal helminths risk factors for developing active tuberculosis

Objectives  To determine the prevalence of intestinal helminth infections in active tuberculosis patients and their healthy household contacts and to assess its association with active TB in an area endemic for both types of infections.

Low dose chronic Schistosoma mansoni infection increases susceptibility to Mycobacterium bovis BCG infection in mice

The incidence of mycobacterial diseases is high and the efficacy of Bacillus Calmette Guérin (BCG) is low in most areas of the world where chronic worm infections are common. However, if and how concurrent worm infections could affect immunity to mycobacterial infections has not been elucidated. In this study we investigated whether infection of mice with Schistosoma mansoni could affect the ability of the animals to control Mycobacterium bovis BCG infection and the immune response to mycobacterial antigens. BALB/c mice subclinically infected with S. mansoni were challenged with M. bovis BCG via the intravenous route. The ability of the animals to contain the replication of M. bovis BCG in their organs, lung pathology as well as the in vitro mycobacterial and worm antigen induced immune responses were evaluated. The results showed that S. mansoni coinfected mice had significantly higher levels of BCG bacilli in their organs and sustained greater lung pathology compared to Schistosoma uninfected controls. Moreover, Schistosoma infected mice show depressed mycobacterial antigen specific Th1 type responses. This is an indication that chronic worm infection could affect resistance/susceptibility to mycobacterial infections by impairing mycobacteria antigen specific Th1 type responses. This finding is potentially important in the control of TB in helminth endemic parts of the world.

Chronic helminth infections may negatively influence immunity against tuberculosis and other diseases of public health importance

Tuberculosis (TB) has once again become a major public health threat owing to the combined effects of deteriorating socioeconomic situations and the emergence of the HIV/AIDS pandemic. The only vaccine available against TB, although effective in reducing the burden of childhood TB, shows enormous variability in its efficacy against pulmonary TB, which is the most common form of the disease in adults. Most areas of high TB incidence and poor TB vaccine efficacy have a high prevalence of intestinal helminth infections. Such infections have been shown to cause a range of immunomodulation characterized by enhanced T helper 2-type cytokine profile, high immunoglobulin E levels and upregulated regulatory T-cell activity, as well as chronic immune activation. An altered background immune profile could have adverse effects on the outcome of subsequent infections and vaccinations. In support of this hypothesis, studies conducted in animals and humans living in worm-endemic areas have shown that helminths impair resistance against a number of infections of major public health importance, including TB, malaria and HIV/AIDS. Understanding such interactions could assist in the design of vaccines against these diseases.

Live Leishmania promastigotes can directly activate primary human natural killer cells to produce interferon‐gamma

Natural killer (NK) cells have been implicated in the natural protection and healing of leishmaniasis by their ability to secrete the macrophage activating cytokine interferon (IFN)γ. Previous studies have demonstrated that early production of interleukin (IL)‐12 triggers IFNγ secretion by NK cells. Here we report that live Leishmania promastigotes (the form that is injected by the vector) can directly induce human peripheral blood NK cells from healthy donors to IFNγ secretion in the absence of IL‐12 and professional antigen presenting cells. Killing of promastigotes abolishes this property. This novel mechanism of activation of the innate immune response may be relevant for establishment of infection and thus also the design of vaccines against leishmaniasis.

Helminthes could influence the outcome of vaccines against TB in the tropics

Helminthes, infections widespread in the tropics, are known to elicit a wide range of immunomodulation characterized by dominant Th2 type immune responses, chronic immune activation as well as up‐regulated regulatory T cell activity. Such a wide range of immunomodulation caused by helminthes may have an impact on the hosts ability to cope with subsequent infections and/or may affect the efficacy of vaccination. Indeed studies conducted in humans living in helminth‐endemic areas and in animal models showed that helminth infection makes the host more permissive to mycobacterial infections and less able to benefit from vaccination. These observations have fundamental practical consequences if confirmed by large and appropriately controlled clinical studies. Eradication of worms could offer an affordable, simple and novel means to reduce the burden of the tuberculosis problem that at the moment seems to be getting out of control in sub‐Saharan Africa. This information would also be of great relevance in the design of vaccines against diseases of major public health importance, including malaria and HIV/AIDS.

HIV-1 alters T helper cytokines, interleukin-12 and interleukin-18 responses to the protozoan parasite Leishmania donovani.

ObjectiveTo investigate the in vitro and in vivo effect of HIV-1 on lymphoproliferative and T helper (Th) cytokine responses in leishmaniasis. MethodsTh1 [interleukin (IL)-2 and interferon (IFN)-γ] and Th2 (IL-4 and IL-10) as well as IFN-γ-inducing cytokines (IL-12 and IL-18) were measured in antigen and mitogen-stimulated culture supernatants of peripheral blood mononuclear cells (PBMC) of healthy donors, HIV-infected and visceral leishmaniasis (VL) patients with or without HIV co-infection. ResultsProliferative responses to phytohaemagglutinin (PHA) were significantly lower in PBMC from VL and asymptomatic HIV-infected persons compared with responses in healthy individuals. VL–HIV co-infected patients showed the lowest responses. Although there was no significant difference in the Leishmania-induced proliferative responses among the healthy group and those infected with HIV only, VL patients (with or without HIV) exhibited very low proliferation. When cultured with PHA or Leishmania, PBMC from healthy donors produced high levels of a Th1 cytokine (IFN-γ) and low levels of Th2 cytokines (IL-4 and IL-10). In addition, co-culturing PBMC from healthy donors with a killed HIV preparation abrogated the production of IFN-γ induced by Leishmania and augmented IL-4 and IL-10 production. Cells from HIV-infected patients produced low levels of IFN-γ, but high levels of IL-10. The addition of anti-IL-10 did not increase Leishmania-induced proliferative responses or IFN-γ production. Both IL-12 and/or IL-18 responses were lower in VL patients, HIV-infected, or VL–HIV co-infected patients as compared with those of healthy donors. ConclusionThe data suggest that the inhibitory effect of HIV and VL on proliferation and IFN-γ production is not due to IL-10 alone, but that the defect induced by HIV and VL probably operates at the level of regulation of IFN-γ-inducing factors, such as IL-12 and IL-18.