Exploring the Coinfection - Underlying Mechanisms


By Sophie Marie Arnim

 Exploring the Helminth and Tuberculosis Marriage 

The immune responses to different pathogens vary according to the type of pathogen that is intruding a host. The type of TLR (Toll-like receptor) that the pathogen triggers will determine the type of response the APC (Antigen presenting cells) needs to make, and this then determines the type of adaptive response initiated.
The innate immune response to intracellular bacteria, like Mycobacterium tuberculosis (Mtb), is mediated mainly by phagocytes and natural killer (NK) cells but the major protective immune response against intracellular bacteria is TH1 cell mediated. Defense against many helminthic infections is mediated by the activation of TH2 cells, which results in production of IgE antibodies and activation of eosinophils (Abbas 2015, p.353)

The innate and adaptive immune responses to helminth infection

 The innate immune response includes that phagocytes attack helminthic parasites and secrete microbicidal substances to kill organisms that are too large to be phagocytosed. Many helminths however have thick teguments that make them resistant to the cytocidal mechanisms of neutrophils and macrophages. They are too large to be ingested by phagocytes. Some helminths may activate the alternative pathway of the complement system, however some parasites appear to have developed resistance to complement-mediated lysis (Abbas 2015, p.352).
Helminths stimulate differentiation of naive CD4+ T cells to the TH2 subset of effector cells, which secrete IL-4 and IL-5. IL-4 stimulates the production of IgE, which binds to the Fcε receptor of eosinophils and mast cells, and IL-5 stimulates the development and activation of eosinophils. IgE coats the parasites, and eosinophils bind to the IgE and cause degranulation, which act to destroy the helminths. The combined actions of mast cells and eosinophils contribute to expulsion of the parasites from the intestine along with other mechanism. The expulsion of some intestinal nematodes may be due to IL-4-dependent mechanisms such as increased peristalsis and does not require IgE (Abbas 2015, p.353).

The innate and adaptive immune responses to Mycobacterium tuberculosis

The innate immune response to intracellular bacteria like Mtb is mediated mainly by phagocytes and natural killer (NK) cells. Intracellular bacteria activate NK cells by inducing expression of NK cell-activating ligands on infected cells and by stimulating dendritic cell and macrophage production of IL-12 and IL-15, both of which are NK cell-activating cytokines. The NK cells produce IFN-γ, which in turn activates macrophages and promotes killing of the phagocytosed bacteria (Abbas 2015, p.344). 
NK cells provide an early defense against these microbes, before the development of adaptive immunity. CD4+ T cells activate phagocytes through the actions of CD40 ligand and IFN-γ, resulting in killing of microbes that are ingested by and survive within phagocytes, and CD8+ cytotoxic T lymphocytes (CTLs) kill infected cells, eliminating microbes that escape the killing mechanisms of phagocytes. CD4+ T cells differentiate into TH1 effectors under the influence of IL-12, which is produced by macrophages and dendritic cells. The T cells express CD40 ligand and secrete IFN-γ, and these two stimuli activate macrophages to produce several microbicidal substances, including reactive oxygen species, nitric oxide, and lysosomal enzymes. In mice, IFN-γ also stimulates the production of antibody isotypes that activate complement and opsonise bacteria for phagocytosis, thus aiding the effector functions of macrophages. The stimuli for the production of these antibodies in humans are not as well defined. The importance of IL-12 and IFN-γ in immunity to intracellular bacteria has been demonstrated in experimental models and in congenital immunodeficiencies (Abbas 2015, p.345)

Cytokine Milieu and Macrophage Development

IFN-γ stimulation induces classically induced macrophages (CAMs) which up-regulate nitric oxide synthase (NOS2), which oxidises L-arginine to NO and citrulline. NO promotes killing of intracellular Mtb.  
Stimulation with IL-4 and IL-13 induce alternatively activated macrophages (AAMs). In AAMs arginase-1 (ARG-1) expression is induced to repair tissue damages. NOS2 and ARG-1 compete for the same substrate, inhibit each other’s expression, and are functionally divergent in their ability to control Mtb replication.
The induction of AAMs in helminth affected lungs was shown to increase Mtb bacterial burden in Nippostrongylus brasiliens infected mice (Potian 2011, p.1866). For further details on the study see the article on critical appraisal. 


Studies on helminth infection and active pulmonary tuberculosis or latent tuberculosis infection (LTBI) 

Very few studies have been performed examining the immunological effects of helminth co-infections on active pulmonary TB (Tuberculosis). These few studies however indicate that helminths modulate the host immune response in active disease (Babu and Nutman 2016, p.602). 
  • For example, it has been shown that intestinal helminth co-infection is accompanied by lowered in vitro production of IFN-γ and elevated production of IL-10 in individuals with active pulmonary tuberculosis [1]. 
  • It was shown that helminth infections with coincident active TB have marked decreases in dual-functional TH1 and TH17 cell frequencies [3] which, in one study at least, may be associated with increased Treg and TH2 responses [2]. 
The major immunological effects of helminth co-infection on immune responses to TB antigens in humans has been primarily demonstrated in vitro. A variety of studies from different endemic areas of the world, using different co-infecting helminth species, have repeatedly shown a significant effect of the presence of helminth infection on the quality of immune response engendered by mycobacteria (Babu and Nutman 2016, p.602). 
  • In vitro studies have shown that pre-exposure of APCs to filarial parasites limit the maturation and pro-inflammatory responses of APCs (DCs and macrophages) in response to subsequent TB infection [4]. 
  • In LTBI, coincident filarial infections have been shown to have a major immunological impact on the Mtb-antigen specific immune responses. TH1 and TH17 responses to Mtb purified protein derivative (PPD) and Mtb secreted proteins were significantly lower in LTBI individuals with concomitant filarial infections, compared to those without filarial infections, in an ex vivo study [5]. Th1 and Th17 down modulation is at least partially mediated through the increased expression of the negative co-stimulatory molecules cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) [5]. 
  • Filarial infections have the additional effect of down modulating the expression and function of Toll-like receptors (TLR), specifically TLR2 and TLR9 [8] and are also known to modulate the immune response to Mtb antigens through an expansion of CD4+ IL-4+ memory T cells, which presumably down regulates the expansion of Th1 cells, via a TH1-TH2 crosstalk [9]. 
  • Hookworm infections have been shown to exert a profound inhibitory effect on protective TH1 and TH17 responses, thus potentially modulating the cytokine environment in which TB is controlled in LTBI [10]. 
  • Strongyloides and Mtb coinfection have been shown to be associated with significantly lower systemic levels of type 1 (IFN-γ, TNF-α, and IL-2) and TH17 (IL- 17A and IL-17F) cytokines, and significantly elevated systemic levels of regulatory (IL-10 and TGFb) and type 2 (IL-4, IL-5, and IL-13) cytokines ex vivo [11]. 
  • A study of immigrants to the United Kingdom demonstrated that helminth infections (mainly Schistosoma mansoni and S. stercoralis) were associated with a decreased frequency of CD4+ IFN-γ-secreting T cells and an increased frequency of CD4+ Treg cells in those with LTBI in comparison to helminth-uninfected controls [12]. Interestingly, following antihelmintic treatment, the frequency of Th1 cells increased and that of Treg cells decreased, indicating that the modulation of T cell responses was helminth-mediated. 
These studies, in aggregate, suggest that helminth infections can modulate a variety of Mtb-specific responses. Currently it is unclear whether this modulation leads to the development of active tuberculosis but human in vitro studies clearly demonstrate a major influence of helminth infections on host responses to TB. A summary of the cytokine regulation of tuberculosis infection by helminths is visualised in Figure 1(Babu and Nutman (2016), p.603).
Figure 1. Cytokine Regulation of Tuberculosis Infection by Helminths. The cytokine responses during relatively acute (early) and chronic helminth infections are depicted on the left. The cytokine responses induced in latent and active tuberculosis are shown on the right. Type 1 cytokines are represented in red, type 2 cytokines in green, and regulatory cytokines in black. The size of the box represents the magnitude of the response. Helminth infections predominantly induce type 2 and regulatory responses, while the response to tuberculosis infection and disease is predominantly type 1(pro-inflammatory). Abbreviations: IFN, interferon; TNF, tumor necrosis factor; TGF, transforming growth factor; IL, Interleukin. Modified from Babu and Nutman (2016)  p. 603.







 Four Recently Suggested Mechanisms of Immune Response Modulation

1) A study on mice infected with Nippostrongylus brasiliensis and airborne Mtb showed the establishment of a type 2 cytokine milieu in the lung that facilitates the development of alternatively activated macrophages (AAM) [13]. Intracellular persistence of Mtb is enhanced by the TH2 response, which is partially mediated by AAM via the IL-4Rα singling pathway (Potian et al. 2011).  

2) Another mechanism by which helminths modulate the immune response to TB is by the production of TGF-β, which can mediate the suppression of TH1 responses in mice, resulting in higher bacterial burdens and decreased delayed-type Th1 hypersensitivity responses [14]. 

3) The third mechanism at play is a direct effect on T cells with decreased TH17 responses and increased expression of CTLA-4 [15].

4) The expression of arginase-1 during coinfections has been shown to mediate impaired TH1 responses to Mtb antigens and exacerbated pulmonary pathology [16]. 

Animal models exploring the mechanisms underlying immune interactions in co-infection clearly reveal the complexity of co-infection. Through which various pathways helminths infection can impact immune responses is summarised in Figure 2. 



 Figure 2. Modulation of Immune Response to Tuberculosis Infection by Helminths Based on Murine Models. Helminth parasites induce the release of alarmin cytokines (thymic stromal lymphopoietin (TSLP), IL-25, and IL-33) from barrier cells. These cytokines then activate a variety of secondary cell types. Helminth parasites or their excretory–secretory products can directly interact with dendritic cells, macrophages, basophils, and eosinophils to induce activation and initiation of the type 2 immune response. This subsequently modulates the T cell response to effect influence on Mycobacterium tuberculosis (Mtb) infection and disease through a variety of mechanisms described. Possibly positive immune responses are on green background, note that through the helminth infection the TH1 and TH17 cells are down-regulated. The immune responses increasing TH2 and Treg cell occurrence are on red background as they are associated with a negative impact on Mtb infection. Abbreviations: arg-1, arginase-1; CTLA-4, cytotoxic T lymphocyte associated protein-4; DC-SIGN, dendritic cell specific intracellular adhesion molecule-3 grabbing non-integrin; IDO, indoleamine 2,3 dioxygenase; IFN, interferon; IL, interleukin; ILC-2, type 2 innate lymphoid cells; PD1, programmed cell death protein 1; TGF, transforming growth factor, TNF, tumor necrosis factor; TSLP, thymic stromal lymphopoietin.Modified from Babu and Nutman (2016) p. 604.

 In conclusion we may say tuberculosis seems to be the only one benefiting from this unusual marriage.

References

Abbas, Abul K (2015) Cellular and molecular immunology. Elsevier, Saunders. Philadelphia, USA.


 Babu, S. and Nutman, T.B. (2016) Review. Helminth-Tuberculosis Co-infection: An Immunologic Perspective. Trends in Immunology, Vol. 37, No. 9.

Potian, J.A. et al. (2011) Preexisting helminth infection induces inhibition of innate pulmonary anti-tuberculosis defense by engag-ing the IL-4 receptor pathway. J. Exp. Med. 208, 1863–1874



References 1 to 16 have been cited from the Babu and Nutman (2016) Review.

  1. Resende Co, T. et al. (2007) Intestinal helminth coinfection has a negative impact on both anti-Mycobacterium tuberculosis immu-nity and clinical response to tuberculosis therapy. Clin. Exp. Immu-nol. 147, 45–52
  2. Abate, E. et al. (2015) Asymptomatic helminth infection in active tuberculosis is associated with increased regulatory and Th-2 responses and a lower sputum smear positivity. PLoS Negl. Trop. Dis. 9, e0003994 
  3. George, P.J. et al. (2014) Helminth infections coincident with active pulmonary tuberculosis inhibit mono- and multifunctional CD4+ and CD8+ T cell responses in a process dependent on IL-10. PLoS Pathog. 10, e1004375 
  4. Talaat, K.R. et al. (2006) Preexposure to live Brugia malayi micro-filariae alters the innate response of human dendritic cells to Mycobacterium tuberculosis. J. Infect. Dis. 193, 196–204
  5. Babu, S. et al. (2009) Human type 1 and 17 Responses in latent tuberculosis are modulated by coincident filarial infection through cytotoxic T lymphocyte antigen-4 and programmed death-1. J. Infect. Dis. 200, 288–298  
  6. Soboslay, P.T. et al. (1992) Ivermectin-facilitated immunity in onchocerciasis. Reversal of lymphocytopenia, cellular anergy and deficient cytokine production after single treatment. Clin. Exp. Immunol. 89, 407–413  
  7. Steel, C. et al. (1991) Immunologic responses to repeated iver-mectin treatment in patients with onchocerciasis. J. Infect. Dis. 164, 581–587 
  8. Babu, S. et al. (2009) Attenuation of toll-like receptor expression and function in latent tuberculosis by coexistent filarial infection with restoration following antifilarial chemotherapy. PLoS Negl. Trop. Dis. 3, e489
  9. Chatterjee, S. et al. (2015) Filarial infection modulates the immune response to Mycobacterium tuberculosis through expansion of CD4+ IL-4 memory T cells. J. Immunol. 194, 2706–2714
  10. George, P.J. et al. (2013) Modulation of mycobacterial-specific Th1 and Th17 cells in latent tuberculosis by coincident hookworm infection. J. Immunol. 190, 5161–5168 
  11. George, P.J. et al. (2015) Modulation of pro- and anti-inflammatory cytokines in active and latent tuberculosis by coexistent Strong-yloides stercoralis infection. Tuberculosis (Edinb) 95, 822–828 
  12. Toulza, F. et al. (2016) Mycobacterium tuberculosis-specific CD4 (+) T-cell response is increased, and Treg cells decreased, in anthelmintic-treated patients with latent TB. Eur. J. Immunol. 46, 752–761  
  13. Potian, J.A. et al. (2011) Preexisting helminth infection induces inhibition of innate pulmonary anti-tuberculosis defense by engag-ing the IL-4 receptor pathway. J. Exp. Med. 208, 1863–1874 
  14. Obieglo, K. et al. (2016) Chronic gastrointestinal nematode infec-tion mutes immune responses to mycobacterial infection distal to the gut. J. Immunol. 196, 2262–2271 
  15. Dias, A.T. et al. (2011) Lower production of IL-17A and increased susceptibility to Mycobacterium bovis in mice coinfected with Strongyloides venezuelensis. Mem. Inst. Oswaldo Cruz 106, 617–619 
  16. Monin, L. et al. (2015) Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis. J. Clin. Invest. 125, 4699–4713

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