ReviewImmunology of mycobacterial infections: With special reference to Mycobacterium avium subspecies paratuberculosis
Introduction
Mycobacterial infections constitute a major threat to human and animal populations worldwide. Tuberculosis has remained the single largest infectious disease causing high mortality in humans for centuries. Major mycobacterial infections of animals are paratuberculosis (Mycobacterium avium subspecies paratuberculosis, MAP) and tuberculosis (Mycobacterium bovis). MAP infection leads to wasting syndrome, which finally progresses to clinical disease, emaciation and death. Paratuberculosis has worldwide distribution (Stabel, 2007), resulting in estimated losses of $200 million in the US alone (Ott et al., 1999) and is one of the most costly infectious diseases of animals (Hasonova and Pavlik, 2006). Rising incidence of paratuberculosis in the past 10 years, however, suggests that these figures underestimate the current financial burden of this disease (Stabel, 2007).
Crohn's disease (CD) is a chronic inflammatory disorder of human gastrointestinal tract and has unknown etiology, but is most likely induced by mucosal exposure to an infecting organism in genetically susceptible individuals where a persistent Th1-driven CMI is elicited (Elson, 2002). MAP is considered to be involved in pathogenesis of CD, since CD shares clinical and histological similarities with animal paratuberculosis (Greenstein and Collins, 2004). Unlike leprosy, CD and MAP appear to have met four Koch's postulates (Greenstein, 2003). MAP DNA has been identified in Crohn's intestinal tissues (Romero et al., 2005) and in circulating leukocytes (Naser et al., 2004). Viable MAP has been cultured from intestinal tissues, blood and milk of persons with CD (Singh et al., 2007; Naser et al., 2004). Antibody response to MAP-specific antigens has also been identified in CD patients (Nakase et al., 2006; Naser et al., 2000). Mishina et al. (1996) reported the presence of MAP RNA in all CD patients. Anti-MAP therapy (rifabutin, clofazimine and clarithromycin) resulted in profound effects on mucosal healing as demonstrated by longitudinal scarring and histological repair (Broody et al., 2007). Such healing of CD-affected intestine has not been seen with standard anti-inflammatory and immunosuppressant drugs (Broody et al., 2007). In one study by Chamberlin et al. (2007), there was clinical remission from CD after antibiotic treatment directed against MAP (clarithromycin, rifabutin and levofloxacin). Greenstein et al. (2007) confirmed that methotrexate and 6-mercaptopurine (standard anti-inflammatory drugs used to treat inflammatory bowel disease (IBD) have MAP inhibitory effects and they hypothesized that clinical efficacy of methotrexate and 6-MP in IBD may be simply due to inhibition of MAP growth and decrease in pro-inflammatory cytokines (thought to be the primary mechanism of action), which may simply be a normal, secondary, physiological response. Though with available evidence it appears that MAP does play some role in CD pathogenesis, further researches are required to prove this hypothesis and we need to use improved culture systems available together with modern molecular methods. In this area, a recently introduced method based on nanotechnology (Kaittanis et al., 2007) utilizing nano-probes specific to MAP will be very useful.
Microbes and immune system are co-evolved. It no longer makes sense to discuss an infectious disease without addressing how the immune system responds to the microbe and how microbial molecules in turn modulate immune response. During mycobacterial infections, a deviation from proper immune response arises disrupting the host's ability to contain bacilli and finally the disease progresses from a long sub-clinical phase to the clinical phase. Sub-clinical stage of paratuberculosis is characterized by undetectable levels of MAP-specific antibodies, increasing IFNγ responses and undetectable to low quantities of bacilli shed in feces. Abundant serum antibodies, decreasing IFNγ response and higher number of bacilli shed in feces, characterize clinical paratuberculosis. This review focuses on the patterns of immune response in the three main stages of MAP infection (early infection, sub-clinical infection and clinical disease) and pathogenesis.
Section snippets
Early infection
MAP like other mycobacteria is an intracellular pathogen infecting and surviving within macrophages and redirecting host immune responses to make a safe heaven.
Sub-clinical infection
Hallmarks of early sub-clinical MAP infection are lack of clinical symptoms, infrequent, low-level shedding of bacteria, and often an undetectable to low serum antibody titer that is predominantly of the IgGl isotype (Valentin and Goethe, 1999). It is during the sub-clinical phase that MAP infection is most difficult to diagnose. If an efficient CMI is maintained, animals may recover from the infection. Experimental inoculation studies in goats revealed that in some of the animals, after the
Clinical infection
Clinical stage of paratuberculosis is represented by extensive damage to intestinal epithelia and severe thickening of the intestinal wall with numerous granulomas (Corpa et al., 2000). Animals are no longer able to process feed properly and severe diarrhea and emaciation ensue. In late sub-clinical and clinical stages of paratuberculosis, infected animals also shed considerable numbers of MAP bacilli in milk and colostrum (Sweeney et al., 1992; Streeter et al., 1995). Thus milk and fecal PCR
Summary
Paratuberculosis is a major animal health and production problem and, also due to the rising concerns of its zoonotic importance, it is essential to have deep and complete understanding of the infection biology to design efficacious vaccine and other control strategies for this devastating infection. From the above discussion it is clear that misdirected immune response due to host modulation by MAP leads to establishment of this debilitating disease. Inhibition of phagosomal maturation,
References (138)
- et al.
IgG, IgM and IgA in the serum of cattle naturally infected with Mycobacterium paratuberculosis
Comp. Immunol. Microbiol. Infect. Dis.
(1988) - et al.
Increased intestinal TNF-α, IL-1β and IL-6 expression in ovine paratuberculosis
Vet. Immunol. Immunopathol.
(1996) γδ T cells and Mycobacterium tuberculosis
Microbes Infect.
(1999)- et al.
A study of immunological responses of sheep clinically-affected with paratuberculosis (Johne's disease). The relationship of blood, mesenteric lymph node and intestinal lymphocyte responses to gross and microscopic pathology
Vet. Immunol. Immunopathol.
(1998) - et al.
Interferon-gamma and interleukin-2 release by lymphocytes derived from the blood, mesenteric lymph nodes and intestines of normal sheep and those affected with paratuberculosis (Johne's disease)
Vet. Immunol. Immunopathol.
(1999) - et al.
Antibody bound to the surface antigen MPB83 of Mycobacterium bovis enhances survival against high dose and low dose challenge
FEMS Immunol. Med. Microbiol.
(2004) - et al.
Relationship between Mycobacterium avium subspecies paratuberculosis, IL-1α, and TRAF1 in primary bovine monocyte-derived macrophages
Vet. Immunol. Immunopathol.
(2007) - et al.
The cellular immunology of bovine paratuberculosis; the predominant response is mediated by cytotoxic gamma/delta T lymphocytes which prevent CD4+activity
Microb. Pathogenesis
(1992) Paratuberculosis and molecular biology
Vet. J.
(1997)- et al.
Classification of lesions observed in natural cases of paratuberculosis in goats
J. Comp. Pathol.
(2000)