Daniel Elias

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.

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.

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.

Nitric oxide production in the exhaled air of patients with pulmonary tuberculosis in relation to HIV co-infection

BackgroundNitric oxide (NO) is essential for host defense in rodents, but the role of NO during tuberculosis (TB) in man remains controversial. However, earlier observations that arginine supplementation facilitates anti-TB treatment, supports the hypothesis that NO is important in the host defense against TB. Local production of NO measured in fractional exhaled air (FeNO) in TB patients with and without HIV co-infection has not been reported previously. Thus, our aim was to investigate levels of FeNO in relation to clinical symptoms and urinary NO metabolites (uNO).MethodsIn a cross sectional study, FeNO and uNO were measured and clinical symptoms, chest x-ray, together with serum levels of arginine, tumor necrosis factor alpha (TNF-alpha) and interleukin 12 (IL-12) were evaluated in sputum smear positive TB patients (HIV+/TB, n = 36, HIV-/TB, n = 59), their household contacts (n = 17) and blood donors (n = 46) from Gondar University Hospital, Ethiopia.ResultsThe proportion of HIV-/TB patients with an increased FeNO level (> 25 ppb) was significantly higher as compared to HIV+/TB patients, but HIV+/TB patients had significantly higher uNO than HIV-/TB patients. HIV+ and HIV-/TB patients both had lower levels of FeNO compared to blood donors and household contacts. The highest levels of both uNO and FeNO were found in household contacts. Less advanced findings on chest x-ray, as well as higher sedimentation rate were observed in HIV+/TB patients as compared to HIV-/TB patients. However, no significant correlation was found between FeNO and uNO, chest x-ray grading, clinical symptoms, TNF-alpha, IL-12, arginine levels or sedimentation rate.ConclusionIn both HIV negative and HIV co infected TB patients, low levels of exhaled NO compared to blood donors and household were observed. Future studies are needed to confirm whether low levels of exhaled NO could be a risk factor in acquiring TB and the relative importance of NO in human TB.