Aggravated infection in mice co-administered with Mycobacterium tuberculosis and the 27-kDa lipoprotein
Avi-Hai Hovav1, Jacob Mullerad, Alexander Maly
1Department of Clinical Microbiology, Faculty of Medicine, Hebrew University, Jerusalem, Israel.
Abstract:
We have previously reported that mice immunized with the mycobacterial 27-kDa lipoprotein were more susceptible to Mycobacterium tuberculosis (Mtb) challenge. We also showed that 27-kDa lipoprotein abrogated the protection afforded by the BCG vaccine when administrated together, suggesting that the 27-kDa lipoprotein may modulate the course of experimental mycobacterial infection. In this study, we address the role of the 27-kDa lipoprotein in modulating the immune response to mycobacteria. Our results show that co-administration of BALB/c mice with Mtb and the 27-kDa lipoprotein (Mtb+27kDa), but not its non-acylated form, increases the susceptibility of mice to Mtb infection. Significantly lower DTH reaction and splenocyte proliferation to PPD stimulation were also observed in Mtb+27kDa-infected mice compared to Mtb-infected mice. Furthermore, during infection, splenocytes and purified T cells lost their ability to proliferate in response to concanavalin A stimulation more rapidly in the Mtb+27kDa-infected mice, which was accompanied by high IFN-gamma and NO production, but low TNF-alpha secretion levels. Addition of L-NMMA, anti-IFN-gamma and anti-TNF-alpha antibodies restored in vitro proliferative responses of T cells from Mtb+27kDa-infected mice. Short-term L-NMMA treatment of Mtb+27kDa-infected mice prevented the 27-kDa-mediated immunosuppression and increase in susceptibility to Mtb. Altogether, these data suggest that the 27-kDa lipoprotein plays a role in Mtb infection by inducing increased suppression of the immune response due to elevated NO production.
Insights
The mycobacterial 27-kDa lipoprotein increases susceptibility to Mycobacterium tuberculosis (Mtb) infection by suppressing the immune response. This immunosuppression is linked to elevated nitric oxide (NO) production.
Area of Science:
- Immunology
- Microbiology
- Infectious Diseases
Background:
- Previous studies indicated that the mycobacterial 27-kDa lipoprotein enhances susceptibility to Mycobacterium tuberculosis (Mtb) challenge.
- This lipoprotein also abrogated BCG vaccine-induced protection, suggesting a role in modulating mycobacterial infection outcomes.
Purpose of the Study:
- To investigate the role of the 27-kDa lipoprotein in modulating the immune response during mycobacterial infection.
- To elucidate the mechanisms by which the 27-kDa lipoprotein influences Mtb infection susceptibility.
Main Methods:
- Co-administration of BALB/c mice with Mtb and the 27-kDa lipoprotein (Mtb+27kDa).
- Assessment of delayed-type hypersensitivity (DTH) reactions, splenocyte proliferation (to PPD and concanavalin A), and cytokine/nitric oxide (NO) production.
- In vitro and in vivo interventions using L-NMMA, anti-IFN-gamma, and anti-TNF-alpha antibodies.
Main Results:
- Mtb+27kDa infection, but not with the non-acylated form, increased susceptibility to Mtb.
- Mtb+27kDa-infected mice showed reduced DTH reactions and splenocyte proliferation, with impaired T cell proliferation during infection.
- Elevated IFN-gamma and NO production, coupled with low TNF-alpha, were observed in Mtb+27kDa-infected mice.
- L-NMMA treatment reversed the immunosuppression and reduced susceptibility in Mtb+27kDa-infected mice.
Conclusions:
- The 27-kDa lipoprotein plays a significant role in Mtb infection by inducing immunosuppression.
- Elevated nitric oxide (NO) production is a key mechanism underlying the 27-kDa lipoprotein-mediated immune suppression and increased susceptibility to Mtb.
- Targeting NO production may offer a therapeutic strategy against Mtb infection exacerbated by the 27-kDa lipoprotein.
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