New insights into the evasion of host innate immunity by Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb) is an extremely successful intracellular pathogen that causes tuberculosis (TB), which remains the leading infectious cause of human death. The early interactions between Mtb and the host innate immune system largely determine the establishment of TB infection and disease development. Upon infection, host cells detect Mtb through a set of innate immune receptors and launch a range of cellular innate immune events. However, these innate defense mechanisms are extensively modulated by Mtb to avoid host immune clearance. In this review, we describe the emerging role of cytosolic nucleic acid-sensing pathways at the host–Mtb interface and summarize recently revealed mechanisms by which Mtb circumvents host cellular innate immune strategies such as membrane trafficking and integrity, cell death and autophagy. In addition, we discuss the newly elucidated strategies by which Mtb manipulates the host molecular regulatory machinery of innate immunity, including the intranuclear regulatory machinery, the ubiquitin system, and cellular intrinsic immune components. A better understanding of innate immune evasion mechanisms adopted by Mtb will provide new insights into TB pathogenesis and contribute to the development of more effective TB vaccines and therapies.

Abstract licence: CC BY

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     Gutierrez MG, et al. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell. 2004;119:753-766.

     Not in our library10.1016/j.cell.2004.11.038 (opens in a new tab)

112. 112.

     Harris J, et al. T helper 2 cytokines inhibit autophagic control of intracellular Mycobacterium tuberculosis. Immunity. 2007;27:505-517.

     Not in our library10.1016/j.immuni.2007.07.022 (opens in a new tab)

113. 113.

     Alonso S, Pethe K, Russell DG, Purdy GE. Lysosomal killing of Mycobacterium mediated by ubiquitin-derived peptides is enhanced by autophagy. Proc. Natl Acad. Sci. USA. 2007;104:6031-6036.

     Not in our library10.1073/pnas.0700036104 (opens in a new tab)

114. 114.

     Bonilla DL, et al. Autophagy regulates phagocytosis by modulating the expression of scavenger receptors. Immunity. 2013;39:537-547.

     Not in our library10.1016/j.immuni.2013.08.026 (opens in a new tab)

115. 115.

     Jagannath C, et al. Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells. Nat. Med. 2009;15:267-276.

     Not in our library10.1038/nm.1928 (opens in a new tab)

116. 116.

     Ponpuak M, et al. Delivery of cytosolic components by autophagic adaptor protein p62 endows autophagosomes with unique antimicrobial properties. Immunity. 2010;32:329-341.

     Not in our library10.1016/j.immuni.2010.02.009 (opens in a new tab)

117. 117.

     Watson RO, Manzanillo PS, Cox JS. Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway. Cell. 2012;150:803-815.

     Not in our library10.1016/j.cell.2012.06.040 (opens in a new tab)

118. 118.

     Manzanillo PS, et al. The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature. 2013;501:512-516.

     Not in our library10.1038/nature12566 (opens in a new tab)

119. 119.

     Franco LH, et al. The ubiquitin ligase smurf1 functions in selective autophagy of Mycobacterium tuberculosis and anti-tuberculous host defense. Cell Host Microbe. 2017;21:59-72.

     Not in our library10.1016/j.chom.2016.11.002 (opens in a new tab)

120. 120.

     The selective autophagy receptors Optineurin and p62 are both required for zebrafish host resistance to mycobacterial infection. · 2019

     Not checked
121. 121.

     Subrahmanian M, Marimuthu J, Sairam T, Sankaran R. In vitro ubiquitination of Mycobacterium tuberculosis by E3 ubiquitin ligase, MKRN1. Biotechnol. Lett. 2020;42:1527-1534.

     Not in our library10.1007/s10529-020-02873-6 (opens in a new tab)

122. 122.

     Thurston TL, Wandel MP, von Muhlinen N, Foeglein A, Randow F. Galectin-8 targets damaged vesicles for autophagy to defend cells against bacterial invasion. Nature. 2012;482:414-418.

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123. 123.

     Mycobacterium tuberculosis: An Adaptable Pathogen Associated With Multiple Human Diseases · 2018

124. 124.

     Forrellad MA, et al. Virulence factors of the Mycobacterium tuberculosis complex. Virulence. 2013;4:3-66.

     Not in our library10.4161/viru.22329 (opens in a new tab)

125. 125.

     Duan L, Yi M, Chen J, Li S, Chen W. Mycobacterium tuberculosis EIS gene inhibits macrophage autophagy through up-regulation of IL-10 by increasing the acetylation of histone H3. Biochem. Biophys. Res. Commun. 2016;473:1229-1234.

     Not in our library10.1016/j.bbrc.2016.04.045 (opens in a new tab)

126. 126.

     Martinez J, et al. Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins. Nat. Cell Biol. 2015;17:893-906.

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127. 127.

     Köster S, et al. Mycobacterium tuberculosisis protected from NADPH oxidase and LC3-associated phagocytosis by the LCP protein CpsA. Proc. Natl Acad. Sci. USA. 2017;114:E8711-E8720.

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128. 128.

     Zhao Y, Wang Z, Zhang W, Zhang L. MicroRNAs play an essential role in autophagy regulation in various disease phenotypes. Biofactors. 2019;45:844-856.

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129. 129.

     Kim JK, et al. MicroRNA-125a inhibits autophagy activation and antimicrobial responses during mycobacterial infection. J. Immunol. 2015;194:5355-5365.

     Not in our library10.4049/jimmunol.1402557 (opens in a new tab)

130. 130.

     Kumar R, et al. MicroRNA 17-5p regulates autophagy in Mycobacterium tuberculosis-infected macrophages by targeting Mcl-1 and STAT3. Cell. Microbiol. 2016;18:679-691.

     Not in our library10.1111/cmi.12540 (opens in a new tab)

131. 131.

     Mycobacterium tuberculosis-induced miR-155 subverts autophagy by targeting ATG3 in human dendritic cells. · 2018

     Not checked
132. 132.

     Kim JK, et al. MIR144* inhibits antimicrobial responses against Mycobacterium tuberculosis in human monocytes and macrophages by targeting the autophagy protein DRAM2. Autophagy. 2017;13:423-441.

     Not in our library10.1080/15548627.2016.1241922 (opens in a new tab)

133. 133.

     Liu F, et al. MicroRNA-27a controls the intracellular survival of Mycobacterium tuberculosis by regulating calcium-associated autophagy. Nat. Commun. 2018;9:4295.

     Not in our library10.1038/s41467-018-06836-4 (opens in a new tab)

134. 134.

     Galluzzi L, Green DR. Autophagy-independent functions of the autophagy machinery. Cell. 2019;177:1682-1699.

     Not in our library10.1016/j.cell.2019.05.026 (opens in a new tab)

135. 135.

     Kimmey JM, et al. Unique role for ATG5 in neutrophil-mediated immunopathology during M. tuberculosis infection. Nature. 2015;528:565-569.

     Not in our library10.1038/nature16451 (opens in a new tab)

136. 136.

     Chandra P, Kumar D. Selective autophagy gets more selective: Uncoupling of autophagy flux and xenophagy flux in Mycobacterium tuberculosis-infected macrophages. Autophagy. 2016;12:608-609.

     Not in our library10.1080/15548627.2016.1139263 (opens in a new tab)

137. 137.

     Autophagy regulates inflammatory programmed cell death via turnover of RHIM-domain proteins · 2019

     Not checked
138. 138.

     Autophagy: A new strategy for host-directed therapy of tuberculosis · 2018

139. 139.

     Bierne H, Cossart P. When bacteria target the nucleus: The emerging family of nucleomodulins. Cell. Microbiol. 2012;14:622-633.

     Not in our library10.1111/j.1462-5822.2012.01758.x (opens in a new tab)

140. 140.

     Seshadri C, et al. Transcriptional networks are associated with resistance to Mycobacterium tuberculosis infection. PLoS ONE. 2017;12:e0175844.

     Not in our library10.1371/journal.pone.0175844 (opens in a new tab)

141. 141.

     Coussens AK, Wilkinson RJ, Martineau AR. Phenylbutyrate is bacteriostatic against Mycobacterium tuberculosis and regulates the macrophage response to infection, synergistically with 25-hydroxy-vitamin D3. PLoS Pathog. 2015;11:e1005007.

     Not in our library10.1371/journal.ppat.1005007 (opens in a new tab)

142. 142.

     Epigenetic Regulation of Matrix Metalloproteinase-1 and -3 Expression in Mycobacterium tuberculosis Infection · 2017

     Not checked
143. 143.

     Kleinnijenhuis J, et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc. Natl Acad. Sci. USA. 2012;109:17537-17542.

     Not in our library10.1073/pnas.1202870109 (opens in a new tab)

144. 144.

     Kaufmann E, et al. BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell. 2018;172:176-190.

     Not in our library10.1016/j.cell.2017.12.031 (opens in a new tab)

145. 145.

     Chen YC, et al. Histone H3K14 hypoacetylation and H3K27 hypermethylation along with HDAC1 up-regulation and KDM6B down-regulation are associated with active pulmonary tuberculosis disease. Am. J. Transl. Res. 2017;9:1943-1955.

     Not in our library

146. 146.

     Yaseen I, Kaur P, Nandicoori VK, Khosla S. Mycobacteria modulate host epigenetic machinery by Rv1988 methylation of a non-tail arginine of histone H3. Nat. Commun. 2015;6:8922.

     Not in our library10.1038/ncomms9922 (opens in a new tab)

147. 147.

     Jose L, et al. Hypothetical protein Rv3423.1 of Mycobacterium tuberculosis is a histone acetyltransferase. FEBS J. 2016;283:265-281.

     Not in our library10.1111/febs.13566 (opens in a new tab)

148. 148.

     Sharma G, Upadhyay S, Srilalitha M, Nandicoori VK, Khosla S. The interaction of mycobacterial protein Rv2966c with host chromatin is mediated through non-CpG methylation and histone H3/H4 binding. Nucleic Acids Res. 2015;43:3922-3937.

     Not in our library10.1093/nar/gkv261 (opens in a new tab)

149. 149.

     Wei M, et al. NLRP3 activation was regulated by DNA methylation modification during Mycobacterium tuberculosis infection. Biomed. Res. Int. 2016;2016:4323281.

     Not in our library10.1155/2016/4323281 (opens in a new tab)

150. 150.

     Sharma G, et al. Genome-wide non-CpG methylation of the host genome during M. tuberculosis infection. Sci. Rep. 2016;6:25006.

     Not in our library10.1038/srep25006 (opens in a new tab)

151. 151.

     Zheng L, et al. Unraveling methylation changes of host macrophages in Mycobacterium tuberculosis Infection. Tuberculosis. 2016;98:139-148.

     Not in our library10.1016/j.tube.2016.03.003 (opens in a new tab)

152. 152.

     DiNardo A, et al. DNA hyper-methylation during tuberculosis dampens host immune responsiveness. J. Clin. Investig. 2020;130:3113-3123.

     Not in our library10.1172/jci134622 (opens in a new tab)

153. 153.

     Verma D, et al. Anti-mycobacterial activity correlates with altered DNA methylation pattern in immune cells from BCG-vaccinated subjects. Sci. Rep. 2017;7:12305.

     Not in our library10.1038/s41598-017-12110-2 (opens in a new tab)

154. 154.

     Srivastava S, Battu MB, Khan MZ, Nandicoori VK, Mukhopadhyay S. Mycobacterium tuberculosis PPE2 protein interacts with p67phox and inhibits reactive oxygen species production. J. Immunol. 2019;203:1218-1229.

     Not in our library10.4049/jimmunol.1801143 (opens in a new tab)

155. 155.

     Bhat KH, Srivastava S, Kotturu SK, Ghosh S, Mukhopadhyay S. The PPE2 protein of Mycobacterium tuberculosis translocates to host nucleus and inhibits nitric oxide production. Sci. Rep. 2017;7:1-13.

     Not in our library10.1038/srep39706 (opens in a new tab)

156. 156.

     Wang J, et al. Mycobacterium tuberculosis suppresses innate immunity by coopting the host ubiquitin system. Nat. Immunol. 2015;16:237-245.

     Not in our library10.1038/ni.3096 (opens in a new tab)

157. 157.

     The mycobacterial phosphatase PtpA regulates the expression of host genes and promotes cell proliferation · 2017

     Not checked
158. 158.

     Rajalingam K, Dikic I. Snapshot: expanding the ubiquitin code. Cell. 2016;164:1074.

     Not in our library10.1016/j.cell.2016.02.019 (opens in a new tab)

159. 159.
     Corrected

     Ubiquitin in the immune system · 2013

160. 160.

     Li J, Chai QY, Liu CH. The ubiquitin system: a critical regulator of innate immunity and pathogen-host interactions. Cell. Mol. Immunol. 2016;13:560-576.

     Not in our library10.1038/cmi.2016.40 (opens in a new tab)

161. 161.

     Danelishvili L, Babrak L, Rose SJ, Everman J, Bermudez LE. Mycobacterium tuberculosis alters the metalloprotease activity of the COP9 signalosome. mBio. 2014;5:e01278-01214.

     Not in our library10.1128/mbio.01278-14 (opens in a new tab)

162. 162.

     Wang J, et al. The ubiquitin ligase TRIM27 functions as a host restriction factor antagonized by Mycobacterium tuberculosis PtpA during mycobacterial infection. Sci. Rep. 2016;6:34827.

     Not in our library10.1038/srep34827 (opens in a new tab)

163. 163.

     Penn BH, et al. An Mtb-human protein-protein interaction map identifies a switch between host antiviral and antibacterial responses. Mol. Cell. 2018;71:637-648.

     Not in our library10.1016/j.molcel.2018.07.010 (opens in a new tab)

164. 164.

     Barandun J, Delley CL, Weber-Ban E. The pupylation pathway and its role in mycobacteria. BMC Biol. 2012;10:95.

     Not in our library10.1186/1741-7007-10-95 (opens in a new tab)

165. 165.

     Wang L, et al. Host-mediated ubiquitination of a mycobacterial protein suppresses immunity. Nature. 2020;577:682-688.

     Not in our library10.1038/s41586-019-1915-7 (opens in a new tab)

166. 166.

     Davey NE, Morgan DO. Building a regulatory network with short linear sequence motifs: Lessons from the degrons of the anaphase-promoting complex. Mol. Cell. 2016;64:12-23.

     Not in our library10.1016/j.molcel.2016.09.006 (opens in a new tab)

167. 167.

     Groschel MI, Sayes F, Simeone R, Majlessi L, Brosch R. ESX secretion systems: mycobacterial evolution to counter host immunity. Nat. Rev. Microbiol. 2016;14:677-691.

     Not in our library10.1038/nrmicro.2016.131 (opens in a new tab)

168. 168.

     Downregulation of protein kinase C-α enhances intracellular survival of Mycobacteria: role of PknG · 2009

     Not checked
169. 169.

     Zhou B, et al. Targeting Mycobacterium protein tyrosine phosphatase B for antituberculosis agents. Proc. Natl Acad. Sci. USA. 2010;107:4573-4578.

     Not in our library10.1073/pnas.0909133107 (opens in a new tab)

170. 170.

     MptpB Promotes Mycobacteria Survival by Inhibiting the Expression of Inflammatory Mediators and Cell Apoptosis in Macrophages · 2018

     Not checked
171. 171.

     Singh R, et al. Disruption of mptpB impairs the ability of Mycobacterium tuberculosis to survive in guinea pigs. Mol. Microbiol. 2003;50:751-762.

     Not in our library10.1046/j.1365-2958.2003.03712.x (opens in a new tab)

172. 172.

     Prisic S, Husson RN. Mycobacterium tuberculosis serine/threonine protein kinases. Microbiol Spectr. 2014;2:681-708.

     Not in our library10.1128/microbiolspec.mgm2-0006-2013 (opens in a new tab)

173. 173.

     Kim KH, et al. Mycobacterium tuberculosis Eis protein initiates suppression of host immune responses by acetylation of DUSP16/MKP-7. Proc. Natl Acad. Sci. USA. 2012;109:7729-7734.

     Not in our library10.1073/pnas.1120251109 (opens in a new tab)

174. 174.

     Wang L, et al. Oxidization of TGFβ-activated kinase by MPT53 is required for immunity to Mycobacterium tuberculosis. Nat. Microbiol. 2019;4:1378-1388.

     Not in our library10.1038/s41564-019-0436-3 (opens in a new tab)

175. 175.

     Yan N, Chen ZJ. Intrinsic antiviral immunity. Nat. Immunol. 2012;13:214-222.

     Not in our library10.1038/ni.2229 (opens in a new tab)

176. 176.

     Diamond MS, Farzan M. The broad-spectrum antiviral functions of IFIT and IFITM proteins. Nat. Rev. Immunol. 2013;13:46-57.

     Not in our library10.1038/nri3344 (opens in a new tab)

177. 177.

     A Role for IFITM Proteins in Restriction of Mycobacterium tuberculosis Infection · 2015

     Not checked
178. 178.

     Lou J, Wang Y, Zheng X, Qiu W. TRIM22 regulates macrophage autophagy and enhances Mycobacterium tuberculosis clearance by targeting the nuclear factor-multiplicity kappaB/beclin 1 pathway. J. Cell. Biochem. 2018;119:8971-8980.

     Not in our library10.1002/jcb.27153 (opens in a new tab)

179. 179.

     Chauhan S, et al. TRIMs and galectins globally cooperate and TRIM16 and galectin-3 co-direct autophagy in endomembrane damage homeostasis. Dev. Cell. 2016;39:13-27.

     Not in our library10.1016/j.devcel.2016.08.003 (opens in a new tab)

180. 180.

     Hoffpauir, C. T. et al. TRIM14 is a key regulator of the type I interferon response during Mycobacterium tuberculosis infection. https://www.biorxiv.org/content/10.1101/828533v1 (2020).

     Not in our library10.4049/jimmunol.1901511 (opens in a new tab)

181. 181.

     Genome-wide association study identifies two risk loci for tuberculosis in Han Chinese · 2018

     Not checked
182. 182.

     Sassetti CM, Boyd DH, Rubin EJ. Comprehensive identification of conditionally essential genes in mycobacteria. Proc. Natl Acad. Sci. USA. 2001;98:12712-12717.

     Not in our library10.1073/pnas.231275498 (opens in a new tab)

183. 183.

     Sanjana NE, Shalem O, Zhang F. Improved vectors and genome-wide libraries for CRISPR screening. Nat. Methods. 2014;11:783-784.

     Not in our library10.1038/nmeth.3047 (opens in a new tab)

184. 184.

     Marakalala MJ, et al. Inflammatory signaling in human tuberculosis granulomas is spatially organized. Nat. Med. 2016;22:531-538.

     Not in our library10.1038/nm.4073 (opens in a new tab)

185. 185.

     Carow B, et al. Spatial and temporal localization of immune transcripts defines hallmarks and diversity in the tuberculosis granuloma. Nat. Commun. 2019;10:1823.

     Not in our library10.1038/s41467-019-09816-4 (opens in a new tab)

186. 186.

     Gagneux S. Ecology and evolution of Mycobacterium tuberculosis. Nat. Rev. Microbiol. 2018;16:202-213.

     Not in our library10.1038/nrmicro.2018.8 (opens in a new tab)

• The Role of microRNAs and Long Non-Coding RNAs in the Regulation of the Immune Response to Mycobacterium tuberculosis Infection · 2021

  Not checked

• Genome-Wide Gene Expression Analysis of Mtb-Infected DC Highlights the Rapamycin-Driven Modulation of Regulatory Cytokines via the mTOR/GSK-3β Axis · 2021

  Not checked

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.