Scientific background

Scientific background..

By Alice Bayiyana

Tuberculosis, let’s talk about it!

Tuberculosis (TB) is predominantly a pulmonary infection caused by a bacterium Mycobacterium tuberculosis. Unlike the worms, M. tuberculosis is primarily a respiratory pathogen with an intracellular niche in mammalian host macrophages. Typically, the bacterium has a complex cell wall comprising long chain fatty acids, glycolipids, peptidoglycan, proteins, and a slow doubling time (18-24h) (3).

Figure on the right showing the structure of Mycobacterium tuberculosis. Adapted from http://www.slideshare.net/asemshadid9/pbl-2-pod-1

Transmission of the disease occurs when a person with active disease coughs.  Interestingly, not everyone who is infected with gets the disease. Primary TB disease can occur after exposure, and as the result of uncontrolled initial infection. Some people harboring a latent infection act as a reservoirs, however risk factors of reactivation to active disease and subsequent transmission are multifactorial. Susceptibility to and the clinical course of the infection depend on a complex interplay between host, bacterial and environmental factors, such as poverty, malnutrition, overcrowding, and exposure to other pathogens. Prevention of TB has been attributed to administration of the Bacillus Calmette–Guérin (BCG) vaccine, an attenuated strain of M. bovis, although its efficacy is questionable. The organism evades innate immunity rendering adaptive responses critical for control and clearance.

What you need to know about helminths!

Helminths are parasitic worms. The word helminth originates from the Greek word hélmins denoting a kind of worm. Helminths are large multicellular organisms which predominantly affect the mammalian digestive system. They are transmitted through soil and vectors. Often times, helminths are referred to as intestinal worms owing to their host extracellular niche although some reside in the blood vessels (1). Worms can live inside humans and animals, receiving nourishment and protection while disrupting their hosts’ nutrient absorption, causing disease. Long term survival in the host despite strong host immune responses occurs because helminths secrete immunomodulatory products.

Worms predominantly affect the intestines. Adult worms reside in the lumen of the small intestine. Figure adapted from http://www.top10homeremedies.com/home-remedies/home-remedies-intestinal-worms.html

Why tuberculosis and helminths co-infection?

Figure above shows the life cycle of one of the parasitic helminths. Invasion of the lungs (respiratory system) precedes the digestive system implying the need to study and correlate the pathogenesis of Mtb and helminths.

Immune responses during Helminths and TB co-infection

Helminths and tuberculosis coinfections coexist in many parts of the World. Common to both infections is the initial establishment of chronic, often asymptomatic infections after exposure and granuloma formation. Progression to disease occurs when there is fail to control/contain the initial infection, usually in susceptible individuals. Interestingly, the responses induced by helminths and M. tuberculosis are mutually paradoxical.

Figure adapted from https://doi.org/10.2147/ITT.S81892- Immunotherapy for tuberculosis: future prospects.

The nature of immune responses to helminth infections are type 2 responses. FoxP3⁺ T reg cells and anergic T cells are the two regulatory T-cell phenotype responses associated with helminth infection. Contrary to helminth infections, phagocytosis of mycobacteria by alveolar macrophages and dendritic cells initiates the first immune responses characterized by pro-inflammatory cytokines IFNγ, IL-1β, and TNF among others.

Meanwhile, research has revealed that helminth-induced Th2 and Treg responses interrupt on host resistance against M. tuberculosis infection.  Emerging studies also indicate that helminth-induced alternatively activated macrophages contribute to enhanced susceptibility to TB (7). A recent study has shown that experimental downregulation of the Th2-like response to Nippostrongylus brasiliensis suppresses resistance to gastrointestinal nematode infection, pulmonary granulomatous inflammation, and fibrosis. Additionally, Fasciola hepatica tegumental antigens have been shown to induce an M2 Macrophage-like phenotype in vivo (6). 

Diminished Th1 and Th17 responses to mycobacterial antigens in helminth coinfection have been noted. These diminished responses are related to overexpression of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and transforming growth factor beta (TGF-β) and to exaggerated Th2 responses.

Whereas macrophage mannose receptor (MRC1) expression and its endocytic function were selectively downregulated by IFNγ, there is experimental evidence that the earliest responses to the infective forms of helminth infections might actually be pro- inflammatory or of a mixed Th1/Th2 nature (7).

However, in another study, Mtb specific Th1 cell development and recruitment to lungs remained unhampered in a helminth co-infection (3). Hence, the question remains of whether an equilibrium between Th1 and Th2 responses is maintained or complete restoration after treatment of these infections remains unanswered.

References

1.      Pesce, J. T., Ramalingam, T. R., Wilson, M. S., Mentink-Kane, M. M., Thompson, R. W., Cheever, A. W., & Wynn, T. A. (2009). Retnla (relmα/fizz1) suppresses helminth-induced Th2-type immunity. PLoS Pathog, 5(4), e1000393.

2.      Flynn, J. L., Chan, J., & Lin, P. L. (2011). Macrophages and control of granulomatous inflammation in tuberculosis. Mucosal immunology, 4(3), 271-278.

3.      Potian, J. A., Rafi, W., Bhatt, K., McBride, A., Gause, W. C., & Salgame, P. (2011). Preexisting helminth infection induces inhibition of innate pulmonary anti-tuberculosis defense by engaging the IL-4 receptor pathway. Journal of Experimental Medicine, jem-20091473.

4.      Ezenwa, V. O., & Jolles, A. E. (2015). Opposite effects of anthelmintic treatment on microbial infection at individual versus population scales. Science, 347(6218), 175-177.

5.      Moreau, E., & Chauvin, A. (2010). Immunity against helminths: interactions with the host and the intercurrent infections. BioMed Research International, 2010.M. J. G. Farthing, “Immune response-mediated pathology in human intestinal parasitic infection,” Parasite Immunology, vol. 25, no. 5, pp. 247–257, 2003. 

6.      Adams, P. N., Aldridge, A., Vukman, K. V., Donnelly, S., & O'neill, S. M. (2014). Fasciola hepatica tegumental antigens indirectly induce an M2 macrophage‐like phenotype in vivo. Parasite immunology, 36(10), 531-539.

7.      Rafi, W., Ribeiro-Rodrigues, R., Ellner, J. J., & Salgame, P. (2012). Coinfection-helminthes and tuberculosis. Current opinion in HIV and AIDS, 7(3), 239-244.

8.      A. Balic, V. M. Bowles, and E. N. T. Meeusen, “Mechanisms of immunity to Haemonchus contortus infection in sheep,” Parasite Immunology, vol. 24, no. 1, pp. 39–46, 2002.