Helminths and immunity against tuberculosis

Abstract

The efficacy of Bacille Calmette Guerin (BCG) is low and incidence of tuberculosis (TB) is high in those areas where helminths are endemic. Protection against tuberculosis requires strong cell mediated immunity while chronic helminth infections induce responses characterized by dominant Th2 responses as well as up-regulated regulatory T cell activity. Such immunomodulation caused by helminths were shown to result in hyporesponsiveness against unrelated antigens. We hypothesized that chronic helminth infection could affect the ability of the host to control mycobacterial infections andlor the efficacy of vaccination against TB.

This thesis is based on five separate clinical and experimental studies. The first was aimed to assess whether intestinal helminth infections could affect TB specific cellular responses in individuals with prior mycobacterial exposure as well as to investigate the impact of worms on the immunogenicity of BCG vaccination in humans. The result indicates that treatment of intestinal worms results in significant improvement in mycobaterial antigen induced Tcell proliferation and IFN-γ production. Moreover, vaccination with BCG significantly improves PPD specific cellular responses in treated individuals but not in the untreated controls.

The second study examined whether the helminth associated down modulation in cellular immune responses against TB antigens is a reflection of altered immunity against mycobacterial infections. We assessed this using a mouse model where mice were infected with Schistosoma mansoni and later challenged with M. bovis BCG. Later analysis of bacterial loads demonstrated that worms could impair the ability of the animals to contain M. bovis BCG infection. This was associated with low Th1 responses and enhanced Th2 responses.

In the third study we assessed if worm associated reduction in the immunogenicity of BCG observed in the first human study may suggest altered efficacy of BCG vaccination against M. tuberculosis. We infected C57B1/6 mice with S. mansoni and later vaccinated them with BCG. Eight weeks post vaccination; the animals were challenged with M. tuberculosis. Comparison was then made between animals BCG vaccinated in the presence of S. mansoni infection and controls with regard to the load of M. tuberculosis, lung pathology as well as in vitro cellular responses to TB antigens. The result shows that there were significantly higher bacterial loads in the Schistosoma infected group compared to controls. Histological evaluation showed that the lungs of Schistosoma pre-infected mice had more pathologic changes compared to controls. Moreover, in vitro nitric oxide and IFN-γ production were markedly lower in the Schistosoma infected group suggesting that helminths could negatively influence the efficacy of BCG.

In the fourth study we examined whether reduction in the in vitro cellular responses to TB antigens associated with worm infection in humans (study I) as well as the poor immunity against mycobacterial infections observed in animal models (studies II) could support the presence of a link between intestinal helminths and clinical TB. We conducted a casecontrol study and showed strong association between helminths and active TB.

In the last paper we examined the impact of deworming of helminth infected populations on the immunogenicity of BCG vaccination and the mechanisms behind helminth induced immunomodulation that affects immunogenicity of BCG. We recruited volunteers with asymptomatic helminth infection and with no sign of prior infection with mycobacteria. The subjects were randomized to anti-helminthic therapy or placebo treatment. The volunteers were later BCG vaccinated and in vitro immunological analysis was conducted. The result showed that indeed worms do affect the immunogenicity of BCG and this was associated with reduced Th1 responses, high TGF-β secretion but not enhanced Th2 responses.

In conclusion, our results demonstrate that immunomodulation by helminths affects immune responses against TB as well as the immunogenicity of BCG. This is a finding with practical consequences as treatment against helminth could offer a novel means to reduce the burden of TB in areas where worms are endemic.