The exploitation of host autophagy and ubiquitin machinery by Mycobacterium tuberculosis in shaping immune responses and host defense during infection

ABSTRACT Infection of SCID mice with a recombinant murine coronavirus (mouse hepatitis virus [MHV]) expressing the T-cell chemoattractant CXC chemokine ligand 10 (CXCL10) resulted in increased survival and reduced viral burden within the brain and liver compared to those of mice infected with an isogenic control virus (MHV), supporting an important role for CXCL10 in innate immune responses following viral infection. Enhanced protection in MHV-CXCL10-infected mice correlated with increased gamma interferon (IFN-γ) production by infiltrating natural killer (NK) cells within the brain and reduced liver pathology. To explore the underlying mechanisms associated with protection from disease in MHV-CXCL10-infected mice, the functional contributions of the NK cell-activating receptor NKG2D in host defense were examined. The administration of an NKG2D-blocking antibody to MHV-CXCL10-infected mice did not reduce survival, dampen IFN-γ production in the brain, or affect liver pathology. However, NKG2D neutralization increased viral titers within the liver, suggesting a protective role for NKG2D signaling in this organ. These data indicate that (i) CXCL10 enhances innate immune responses, resulting in protection from MHV-induced neurological and liver disease; (ii) elevated NK cell IFN-γ expression in the brain of MHV-CXCL10-infected mice occurs independently of NKG2D; and (iii) NKG2D signaling promotes antiviral activity within the livers of MHV-infected mice that is not dependent on IFN-γ and tumor necrosis factor alpha secretion.

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Inflammasomes inMycobacterium tuberculosis-Driven Immunity

Canadian Journal of Infectious Diseases and Medical Microbiology ◽

10.1155/2017/2309478 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 8

Author(s):

Sebastian Wawrocki ◽

Magdalena Druszczynska

Keyword(s):

Mycobacterium Tuberculosis ◽

Inflammatory Response ◽

Immune Responses ◽

Proinflammatory Cytokines ◽

Immune Cells ◽

Protein Complexes ◽

Inflammasome Activation ◽

Host Immune Responses ◽

Multimeric Protein

The development of effective innate and subsequent adaptive host immune responses is highly dependent on the production of proinflammatory cytokines that increase the activity of immune cells. The key role in this process is played by inflammasomes, multimeric protein complexes serving as a platform for caspase-1, an enzyme responsible for proteolytic cleavage of IL-1βand IL-18 precursors. Inflammasome activation, which triggers the multifaceted activity of these two proinflammatory cytokines, is a prerequisite for developing an efficient inflammatory response against pathogenicMycobacterium tuberculosis(M.tb). This review focuses on the role of NLRP3 and AIM2 inflammasomes inM.tb-driven immunity.

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HTLV-1 infection interferes with immune responses to Mycobacterium tuberculosis antigens

Retrovirology ◽

10.1186/1742-4690-12-s1-o24 ◽

2015 ◽

Vol 12 (S1) ◽

Author(s):

Natália B Carvalho ◽

Maria de Lourdes Bastos ◽

Yuri Neves ◽

Anselmo Souza ◽

Eduardo Martins Netto ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Immune Responses

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Effect of isoniazid preventive therapy on immune responses to mycobacterium tuberculosis: an open label randomised, controlled, exploratory study

BMC Infectious Diseases ◽

10.1186/s12879-015-1201-8 ◽

2015 ◽

Vol 15 (1) ◽

Cited By ~ 16

Author(s):

Irene Andia Biraro ◽

Moses Egesa ◽

Simon Kimuda ◽

Steven G. Smith ◽

Frederic Toulza ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Immune Responses ◽

Exploratory Study ◽

Preventive Therapy ◽

Isoniazid Preventive Therapy ◽

Open Label ◽

Randomised Controlled

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The Mycobacterium tuberculosis PE_PGRS Protein Family Acts as an Immunological Decoy to Subvert Host Immune Response

International Journal of Molecular Sciences ◽

10.3390/ijms23010525 ◽

2022 ◽

Vol 23 (1) ◽

pp. 525

Author(s):

Tarina Sharma ◽

Anwar Alam ◽

Aquib Ehtram ◽

Anshu Rani ◽

Sonam Grover ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Immune Responses ◽

Current Knowledge ◽

Immune Effector ◽

Host Immune Responses ◽

Intrinsically Disordered ◽

Multiple Strategies ◽

Latent Stage ◽

Immune Mediated ◽

Critical Edge

Mycobacterium tuberculosis (M.tb) is a successful pathogen that can reside within the alveolar macrophages of the host and can survive in a latent stage. The pathogen has evolved and developed multiple strategies to resist the host immune responses. M.tb escapes from host macrophage through evasion or subversion of immune effector functions. M.tb genome codes for PE/PPE/PE_PGRS proteins, which are intrinsically disordered, redundant and antigenic in nature. These proteins perform multiple functions that intensify the virulence competence of M.tb majorly by modulating immune responses, thereby affecting immune mediated clearance of the pathogen. The highly repetitive, redundant and antigenic nature of PE/PPE/PE_PGRS proteins provide a critical edge over other M.tb proteins in terms of imparting a higher level of virulence and also as a decoy molecule that masks the effect of effector molecules, thereby modulating immuno-surveillance. An understanding of how these proteins subvert the host immunological machinery may add to the current knowledge about M.tb virulence and pathogenesis. This can help in redirecting our strategies for tackling M.tb infections.

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Mitochondrial fusion mediated by mitofusin 1 regulates macrophage mycobactericidal activity by enhancing autophagy

Infection and Immunity ◽

10.1128/iai.00306-21 ◽

2021 ◽

Author(s):

Yuping Ning ◽

Yi Cai ◽

Youchao Dai ◽

Fuxiang Li ◽

Siwei Mo ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Life Cycle ◽

Atp Synthase ◽

Host Defense ◽

Mitochondrial Dynamics ◽

Critical Role ◽

Mitochondrial Fusion ◽

Atp Production ◽

Metabolism Pathway ◽

Mitofusin 1

Mitochondria as a highly dynamic organelle continuously changes morphology and position during its life cycle. Mitochondrial dynamics including fission and fusion play a critical role in maintaining functional mitochondria for ATP production, which is directly linked to host defense against Mtb infection. However, how macrophages regulate mitochondrial dynamics during Mycobacterium tuberculosis (Mtb) infection remains elusive. In this study, we found that Mtb infection induced mitochondrial fusion through enhancing the expression of mitofusin 1 ( MFN1 ), which resulted in increased ATP production. Silencing MFN1 inhibited mitochondrial fusion and subsequently reduced ATP production, which, in turn, severely impaired macrophages mycobactericidal activity by inhibiting autophagy. Impairment of mycobactericidal activity and autophagy was replicated using oligomycin, an inhibitor of ATP synthase. In summary, our study revealed MFN1-mediated mitochondrial fusion is essential for macrophages mycobactericidal activity through the regulation of ATP dependent autophagy. MFN1-mediated metabolism pathway might be targets for development of host direct therapy (HDT) strategy against TB.

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Evaluation of Immune Responses to a DNA Vaccine Encoding Ag85a-Cfp10 Antigen of Mycobacterium tuberculosis in an Animal Model

Jundishapur Journal of Microbiology ◽

10.5812/jjm.65689 ◽

2018 ◽

Vol In Press (In Press) ◽

Cited By ~ 1

Author(s):

Hadi Peerdogaheh ◽

Roghayeh Teimourpour ◽

Bagher Moradi ◽

Mahdi Yousefipour ◽

Aida Gholoobi ◽

...

Keyword(s):

Animal Model ◽

Mycobacterium Tuberculosis ◽

Immune Responses ◽

Dna Vaccine

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Immune Responses Following BCG Immunization of Infants in Uganda and United Kingdom Are Similar for Purified Protein Derivative but Differ for Secretory Proteins of Mycobacterium tuberculosis

Frontiers in Immunology ◽

10.3389/fimmu.2021.637114 ◽

2021 ◽

Vol 12 ◽

Author(s):

Patrice A. Mawa ◽

Mateusz Hasso-Agopsowicz ◽

Lawrence Lubyayi ◽

Grace Nabakooza ◽

Marjorie Nakibuule ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

United Kingdom ◽

Immune Responses ◽

Secretory Proteins ◽

Birth Cohorts ◽

Bcg Vaccination ◽

Ifn Γ ◽

The Uk ◽

Mycobacterial Antigens ◽

Stimulation Of

Introduction: The immunogenicity of BCG vaccination in infants differs between populations. We hypothesized that prenatal exposure to mycobacterial antigens might explain the differences in immune responses to BCG seen in other studies of infants in Africa and the United Kingdom (UK) and we explored this in birth cohorts in Uganda and the UK.Materials and Methods: Blood samples were obtained from BCG-immunized infants of mothers with (n = 110) and without (n = 121) latent Mycobacterium tuberculosis infection (LTBI) in Uganda and BCG-immunized infants of mothers without LTBI (n = 25) in the UK at 10 and 52 weeks after birth. Cytokine and chemokine responses to PPD were measured to assess responses to BCG immunization, and to ESAT6/CFP10 to assess exposure to or infection with M. tuberculosis or non-tuberculous mycobacteria (NTM) in 6-day whole blood culture supernatants by a 17-plex Luminex assay. Median responses were compared between Ugandan infants (together, and separated by maternal LTBI status) and UK infants.Results: The IFN-γ response to BCG vaccination was similar between Ugandan and UK infants at 10 and 52 weeks. At week 52, TNF production was marginally higher in Ugandan infants, but after adjusting for multiple comparisons this difference was not significant. At weeks 10 and 52, stimulation of blood with ESAT6/CFP10 produced significantly higher IFN-γ, TNF, IL-12p40, IL-1α, IL-1β, IL-1Ra, IP-10, MIP-1α, MIP-1β, and GM-CSF in Ugandan compared to UK infants. Stimulation of blood with ESAT6/CFP10 produced significantly higher amounts of IL-8 (p = 0.0001), IL-10 (p = 0.0022), and IL-13 (p = 0.0020) in the UK than in Ugandan infants of mothers without LTBI at week 10, but not at week 52.Conclusions: Immune responses to mycobacterial antigens following BCG immunization are similar for PPD, but differ for ESAT6/CFP10, between infants in Uganda and the UK. Neither maternal LTBI nor infant exposure to or infection with mycobacteria impacts the response to BCG. The observed global differences in immune response to BCG immunization are likely to be due to other causes.

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