Protective efficacy of Mycobacterium indicus pranii against tuberculosis and underlying local lung immune responses in guinea pig model

Gupta, Ankan; Ahmad, Farhan Jalees; Ahmad, Faiz; Gupta, Umesh Datta; Natarajan, Mohan; Katoch, Vishwa Mohan; Bhaskar, Sangeeta

doi:10.1016/j.vaccine.2012.07.061

Cited by 41 publications

(21 citation statements)

References 43 publications

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“…Analysis of the immune response revealed that MIP promotes the Th1 response and leads to interferon-c production by lung-infiltrating immune cells. 15,16 The whole genome sequence of MIP has been published recently and consistent with our findings in silico analysis demonstrated a much higher fraction of putative antigenic proteins in MIP compared with BCG. 17 Given the importance of Th1 immune response in protection against cancer, we also evaluated MIP for cancer immunotherapy.…”

Section: M M U N O L O G Y O R I G I N a L A R T I C L Esupporting

confidence: 88%

Mycobacterium indicus pranii and Mycobacterium bovis BCG lead to differential macrophage activation in Toll‐like receptor‐dependent manner

et al. 2014

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SummaryMycobacterium indicus pranii (MIP) is an atypical mycobacterial species possessing strong immunomodulatory properties. It is a potent vaccine candidate against tuberculosis, promotes Th1 immune response and protects mice from tumours. In previous studies, we demonstrated higher protective efficacy of MIP against experimental tuberculosis as compared with bacillus Calmette-Gu erin (BCG). Since macrophages play an important role in the pathology of mycobacterial diseases and cancer, in the present study, we evaluated the MIP in live and killed form for macrophage activation potential, compared it with BCG and investigated the underlying mechanisms. High levels of tumour necrosis factor-a, interleukin-12p40 (IL-12p40), IL-6 and nitric oxide were produced by MIP-stimulated macrophages as compared with BCG-stimulated macrophages. Prominent up-regulation of co-stimulatory molecules CD40, CD80 and CD86 was also observed in response to MIP. Loss of response in MyD88-deficient macrophages showed that both MIP and BCG activate the macrophages in a MyD88-dependent manner. MyD88 signalling pathway culminates in nuclear factor-jB/activator protein-1 (NF-jB/AP-1) activation and higher activation of NF-jB/AP-1 was observed in response to MIP. With the help of pharmacological inhibitors and Toll-like receptor (TLR) -deficient macrophages, we observed the role of TLR2, TLR4 and intracellular TLRs in MIP-mediated macrophage activation. Stimulation of HEK293 cells expressing TLR2 in homodimeric or heterodimeric form showed that MIP has a distinctly higher level of TLR2 agonist activity compared with BCG. Further experiments suggested that TLR2 ligands are well exposed in MIP whereas they are obscured in BCG. Our findings establish the higher macrophage activation potential of MIP compared with BCG and delineate the underlying mechanism.

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Section: M M U N O L O G Y O R I G I N a L A R T I C L Esupporting

confidence: 88%

Mycobacterium indicus pranii and Mycobacterium bovis BCG lead to differential macrophage activation in Toll‐like receptor‐dependent manner

et al. 2014

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“…Overall, our studies showed that MIP(L) induced a higher DC activation compared with MIP(K). MIP(L) has also been observed to confer higher protection against experimental TB, and studies in the animal model have shown that MIP(L) does not cause any untoward reaction [15]. Based on the present and previous observations, we suggest further evaluation of MIP(L) for immunotherapy of TB and cancer.…”

Section: Discussionsupporting

confidence: 71%

“…The nonpathogenic nature of MIP has been authenticated by its recently published whole-genome sequence [14]. We previously observed that MIP(L) confers significantly higher protection against M.tb compared with MIP(K) and BCG [15,16]. MIP promoted the Th1 type of immune response in animal models of TB, as indicated by IFN-g production by immune cells from lung and lymphoid tissue.…”

Section: Introductionmentioning

confidence: 97%

Mycobacterium indicus pranii induces dendritic cell activation, survival, and Th1/Th17 polarization potential in a TLR-dependent manner

Kumar

John

Marathe

et al. 2015

Journal of Leukocyte Biology

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MIP is a nonpathogenic, soil-borne predecessor of Mycobacterium avium. It has been reported previously that MIP possesses strong immunomodulatory properties and confers protection against experimental TB and tumor. DCs, by virtue of their unmatched antigen-presentation potential, play a critical role in activation of antitumor and antimycobacterial immune response. The effect of MIP on the behavior of DCs and the underlying mechanisms, however, have not been investigated so far. In the present study, we showed that MIP induces significant secretion of IL-6, IL-12p40, IL-10, and TNF-α by DCs and up-regulates the expression of costimulatory molecules CD40, CD80, and CD86. MIP(L) induced a significantly higher response compared with MIP(K). PI and Annexin V staining showed that MIP increases DC survival by inhibiting apoptosis. Consistently, higher expression of antiapoptotic proteins Bcl-2 and Bcl-xl was observed in MIP-stimulated DCs. Cytokines, produced by naïve T cells, cocultured with MIP-stimulated DCs, showed that MIP promotes Th1/Th17 polarization potential in DCs. Response to MIP was lost in MyD88(-/-)DCs, underscoring the critical role of TLRs in MIP-induced DC activation. Further studies revealed that TLR2 and TLR9 are involved in DC activation by MIP(L), whereas MIP(K) activates the DCs through TLR2. Our findings establish the DC activation by MIP, define the behavior of MIP-stimulated DCs, and highlight the role of TLRs in MIP-induced DC activation.

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“…Mip, given by itself, had only very minor effects on the growth of the infection, but in animals given both treatments no growth of the infection was observed at the 4-week time point. This was followed by a similar study in guinea pigs looking at the immunogenicity of Mip [52]. Animals were vaccinated with live or heat killed preparations of Mip or BCG.…”

Section: Therapeutic Vaccinesmentioning

confidence: 99%

Vaccine Development for Tuberculosis: Current Progress

Orme

2013

Drugs

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Very substantial efforts have been made over the past decade or more to develop vaccines against tuberculosis. Historically, this began with a view to replace the current vaccine, BCG, but more recently most candidates are either new forms of this bacillus, or are designed to boost immunity in children given BCG as infants. Good progress is being made, but very few have as yet progressed into clinical trials. The leading candidate has advanced to Phase IIb efficacy testing, with disappointing results. This article discusses the various types of vaccines, including those designed to be used in a prophylactic setting, either alone or BCG-boosting, true therapeutic [post-exposure] vaccines, and therapeutic vaccines designed to augment chemotherapy. While there is no doubt that progress is still being made, we have a growing awareness of the limitations of our animal model screening processes, further amplified by the fact that we still do not have a clear picture of the immunological responses involved, and the precise type of long lived immunity we will need effective new vaccines to induce.

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Protective efficacy of Mycobacterium indicus pranii against tuberculosis and underlying local lung immune responses in guinea pig model

Cited by 41 publications

References 43 publications

Mycobacterium indicus pranii and Mycobacterium bovis BCG lead to differential macrophage activation in Toll‐like receptor‐dependent manner

Mycobacterium indicus pranii and Mycobacterium bovis BCG lead to differential macrophage activation in Toll‐like receptor‐dependent manner

Mycobacterium indicus pranii induces dendritic cell activation, survival, and Th1/Th17 polarization potential in a TLR-dependent manner

Vaccine Development for Tuberculosis: Current Progress

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