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Oncolytic virus (OV) is increasingly being recognized as a novel vector in cancer immunotherapy. Increasing evidence suggests that OV has the ability to change the immune status of tumor microenvironment, so called transformation of ‘cold’ tumors into ‘hot’ tumors. The improved anti-tumor immunity can be induced by OV and further enhanced through the combination of various immunomodulators. The Neo-2/15 is a newly de novo synthesized cytokine that functions as both IL-2 and IL-15. However, it specifically lacks the binding site of IL-2 receptor α subunit (CD25), therefore unable to induce the Treg proliferation. In present study, a recombinant vesicular stomatitis virus expressing the Neo-2/15 (VSVM51R-Neo-2/15) was generated. Intratumoral delivery of VSVM51R-Neo-2/15 efficiently inhibited tumor growth in mice without causing the IL-2-related toxicity previously observed in clinic. Moreover, treatment with VSVM51R-Neo-2/15 increased the number of activated CD8+T cells but not Treg cells in tumors. More tumor-bearing mice were survival with VSVM51R-Neo-2/15 treatment, and the surviving mice displayed enhanced protection against tumor cell rechallenge due to the induced anti-tumor immunity. In addition, combination therapy of OV and anti-PD-L1 immune checkpoint inhibitors further enhanced the anti-tumor immune response. These findings suggest that our novel VSVM51R-Neo-2/15 can effectively inhibit the tumor growth and enhance the sensitivity to immune checkpoint inhibitors, providing promising attempts for further clinical trials.

Viral myocarditis is a widespread cardiac disease associated with inflammation and myocardial injury and is predominantly caused by coxsackievirus B3 (CVB3) infection in humans as well as in mice. CVB3-induced myocarditis shows sexually dimorphic sensitivity and is more prevalent in male mice. Our previous studies showed that natural killer (NK) cells played an indispensable role in CVB3-induced myocarditis, and female mice exhibited less pathological cardiac interferon gamma (IFN-γ)+NK cell infiltration than did male mice. However, the precise mechanisms were not well elucidated.

TLR7/9 signals are capable of mounting massive interferon (IFN) response in plasmacytoid dendritic cells (pDCs) immediately after viral infection, yet the involvement of epigenetic regulation in this process has not been documented. Here, we report that zinc finger CXXC family epigenetic regulator CXXC5 is highly expressed in pDCs, where it plays a crucial role in TLR7/9- and virus-induced IFN response. Notably, genetic ablation of CXXC5 resulted in aberrant methylation of the CpG-containing island (CGI) within the Irf7 gene and impaired IRF7 expression in steady-state pDCs. Mechanistically, CXXC5 is responsible for the recruitment of DNA demethylase Tet2 to maintain the hypomethylation of a subset of CGIs, a process coincident with active histone modifications and constitutive transcription of these CGI-containing genes. Consequently, CXXC5-deficient mice had compromised early IFN response and became highly vulnerable to infection by herpes simplex virus and vesicular stomatitis virus. Together, our results identify CXXC5 as a novel epigenetic regulator for pDC-mediated antiviral response.

ABSTRACTTuberculosis (TB) remains a major health problem worldwide, and the development of effective vaccines is urgently needed. Vaccination strategies based on heterologous prime–boost protocols using Mycobacterium bovisbacillus Calmette-Guérin (BCG) as primer and modified vaccinia virus Ankara strain expressing the mycobacterial antigen Ag85A (MVA85A) as booster may increase the protective efficacy of BCG. In addition, vaccination with the recombinant viral vaccine vesicular stomatitis virus (VSV)-846 (Rv3615c, Mtb10.4, and Rv2660c) can elicit a remarkable T-cell-mediated immune response and provide an effective long-term protection after the BCG challenge. In this study, we used VSV-846 to boost BCG and evaluated its immunogenicity in BALB/c mice. In this prime–boost approach, boosting with VSV-846 significantly enhanced IFN-γ CD4 T cell responses, which are crucial for anti-TB immune responses. Moreover, VSV-846 boosting significantly reduced pathology compared with mock vaccination, and decreased the bacterial loads in lung tissues compared with BCG or VSV-846 vaccination alone. The analysis of vaccine-induced immunity identified that polyfunctional T cells might contribute to the enhanced protection by VSV-846 boosting. This study proved that viral booster VSV-846 in mice improved the protection against mycobacteria infection, which could be helpful in designing an efficient vaccination strategy against TB in humans.

Viral myocarditis, which is mainly caused by coxsackievirus B3 (CVB3), affects about 5%–20% of the world population and still lacks efficient treatments. Green tea, a tonic and healthful beverage that was originated in ancient China, has been receiving considerable attention for its protective effect on cardiovascular diseases in recent years. In the present investigation, we aimed to explore the effect of green tea polyphenol epigallocatechin-3-gallate (EGCG) on CVB3-induced myocarditis and its underlying mechanism. Our study showed that EGCG could alleviate CVB3-induced myocarditis as evidenced by less cardiac injury and higher survival rate. Furthermore, we found that EGCG failed to downregulate the expression of inflammatory cytokines but could significantly inhibit the replication of CVB3. Furthermore, we found that EGCG treatment could downregulate the protein expression level of coxsackievirus and adenovirus receptor, the major receptor for CVB3 to infect cardiac myocytes. In conclusion, our data indicated that EGCG could ameliorate CVB3-induced myocarditis through inhibiting viral replication, which might provide a potential novel therapeutic strategy for viral myocarditis.

Viral myocarditis, which is mostly caused by coxsackievirus infection, is characterized by myocardial inflammation. Abnormal endoplasmic reticulum (ER) stress participates in many heart diseases, but its role in viral myocarditis remains unsolved.

CCL19, CCL21, CCL24, CCL25, CXCL8, CXCL10, and XCL2 induce M1 macrophage chemotaxis, whereas CCL7 induces chemotaxis of M1 and M2 macrophages. The homing of proinflammatory (M1) and the “alternatively activated” anti‐inflammatory (M2) macrophages plays a different role in the process of inflammation. Chemokines are the major mediators of macrophage chemotaxis, but how they differentially regulate M1 and M2 macrophages remains largely unclear. In the present study, we attempted to screen chemokines that differentially induce chemotaxis of M1 and M2 macrophages and to explore the underlying mechanism. Among the 41 chemokines that specifically bind to 20 chemokine receptors, CCL19, CCL21, CCL24, CCL25, CXCL8, CXCL10, and XCL2 specifically induced M1 macrophage chemotaxis, whereas CCL7 induced chemotaxis of both M1 and M2 macrophages. Whereas the differential effects of these chemokines on M1/M2 macrophage chemotaxis could be attributable to the predominant expression of their cognate receptors on the macrophage subsets, CCR7, the receptor for CCL19/CCL21, appeared to be an exception. Immunoblot analysis indicated an equivalent level of CCR7 in the whole cell lysate of M1 and M2 macrophages, but CCL19 and CCL21 only induced M1 macrophage chemotaxis. Both immunoblot and confocal microscopy analyses demonstrated that CCR7 was predominantly expressed on the cell surface of M1 but in the cytosol of M2 macrophages before ligand stimulation. As a result, CCL19 or CCL21 induced activation of both MEK1‐ERK1/2 and PI3K‐AKT cascades in M1 but not in M2 macrophages. Intriguingly, CCL19/CCL21‐mediated M1 macrophage chemotaxis was blocked by specific inhibition of PI3K rather than MEK1. Together, these findings suggest that recruitment of M1 and M2 macrophages is fine tuned by different chemokines with the involvement of specific signaling pathways.

Coxsackievirus B3 (CVB3) infection is considered as the most common cause of viral myocarditis with no available vaccine. Considering that CVB3 mainly invades through the gastrointestinal mucosa, the development of CVB3-specific mucosal vaccine, which is the most efficient way to induce mucosal immune responses, gains more and more attention. In this study, we used absent in melanoma 2 (AIM2) as a mucosal adjuvant to enhance the immunogenicity and immunoprotection of CVB3-specific chitosan-pVP1 vaccine. Mice were intranasally co-immunized with 50 μg chitosan-pAIM2 and equal amount of chitosan-pVP1 vaccine 4 times at 2 week-intervals, and then challenged with CVB3 2 weeks after the last immunization. Compared with chitosan-pVP1 vaccine immunization alone, chitosan-pAIM2 co-immunization enhanced resistance to CVB3-induced myocarditis evidenced by significantly enhanced ejection fractions from 55.40 ± 9.35 to 80.31 ± 11.35, improved myocarditis scores from 1.50 ± 0.45 to 0.30 ± 0.15, reduced viral load from 3.33 ± 0.50 to 0.50 ± 0.65, and increased survival rate from 40.0% to 75.5%. This increased immunoprotection might be attributed to the augmented level of CVB3-specific fecal SIgA with high affinity and neutralizing ability. In addition, co-immunization with chitosan-pAIM2 remarkably facilitated dendritic cells (DCs) recruitment to mesenteric lymph nodes (MLN), and promoted the expression of IgA-inducing factors (BAFF, APRIL, iNOS, RALDH1, IL-6, TGF-β), which might account for its mucosal adjuvant effect. This strategy may represent a promising prophylactic vaccine against CVB3-induced myocarditis.

Development of effective anti-tuberculosis (TB) vaccines is one of the important steps to improve control of TB. Cell-mediated immune response significantly affects the control of M. tuberculosisinfection. Thus, vaccines able to elicit strong cellular immune response hold special advantages against TB. In this study, three well-defined mycobacterial antigens (Rv3615c, Mtb10.4 [Rv0228], and Rv2660c) were engineered as a novel triple-antigen fusion DNA vaccine p846. The p846 vaccine consists of a high density of CD4+and CD8+T-cell epitopes. Intramuscular immunization of p846 induced robust T cells mediated immune response comparable to that of bacillus Calmette-Guérin (BCG) vaccination but more effective than that of individual antigen vaccination. After mycobacterial challenge, p846 immunization decreased bacterial burden at least 15-fold compared with individual antigen-based vaccination. Notably, the lungs of mice immunized with p846 exhibited fewer inflammatory cell infiltrates and less damage than those of control group mice. Our data demonstrate that the potential of p846 vaccine to protect against TB and the feasibility of this design strategy for further TB vaccine development.

ABSTRACTCoxsackievirus B3 (CVB3), a small single-stranded RNA virus, belongs to the Picornaviridaefamily. Its infection is the most common cause of myocarditis, with no vaccine available. Gastrointestinal mucosa is the major entry port for CVB3; therefore, the induction of local immunity in mucosal tissues may help control initial viral infections and alleviate subsequent myocardial injury. Here we evaluated the ability of high-mobility group box 1 (HMGB1) encapsulated in chitosan particles to enhance the mucosal immune responses induced by the CVB3-specific mucosal DNA vaccine chitosan-pVP1. Mice were intranasally coimmunized with 4 doses of chitosan-pHMGB1 and chitosan-pVP1 plasmids, at 2-week intervals, and were challenged with CVB3 4 weeks after the last immunization. Compared with chitosan-pVP1 immunization alone, coimmunization with chitosan-pHMGB1 significantly (P< 0.05) enhanced CVB3-specific fecal secretory IgA levels and promoted mucosal T cell immune responses. In accordance, reduced severity of myocarditis was observed in coimmunized mice, as evidenced by significantly (P< 0.05) reduced viral loads, decreased myocardial injury, and increased survival rates. Flow cytometric analysis indicated that HMGB1 enhanced dendritic cell (DC) recruitment to mesenteric lymph nodes and promoted DC maturation, which might partly account for its mucosal adjuvant effect. This strategy may represent a promising approach to candidate vaccines against CVB3-induced myocarditis.

A novel tylophorine analog W‐8 enhanced Foxp3 expression through both transcriptional and epigenetic programs, and its ameliorated TNBS induced colitis. Tylophorine and analogs are phenanthroindolizidine alkaloids, several of which have been reported to have anticancer, antiviral, and anti‐inflammatory properties. However, their function in the immune system remains widely unknown. Transcription factor Foxp3 is critical for the development and function of Treg, which down‐regulates the immune system and maintains tolerance to self‐antigens. In the present study, we defined a novel tylophorine analog, W‐8, enhanced TGF‐β‐induced Foxp3 expression at the mRNA and the protein levels. Interestingly, W‐8 synergistically increased the level of TGF‐β‐induced p‐Smad3 through inhibition of the AKT/mTOR pathway and enhanced the demethylation of the promoter region of the Foxp3 through inhibition of the ERK pathway and DNMT1 expression. Moreover, administration of W‐8 suppressed TNBS‐induced murine colitis and increased Tregs in lymphoid tissues. Finally, W‐8 enhanced conversion of naïve T cells to Tregs in vivo. In summary, our results defined a novel compound that enhanced Foxp3 expression through transcriptional and epigenetic programs, and it might serve as a therapeutic agent for inflammatory diseases.

ABSTRACTTuberculosis (TB) caused by Mycobacterium tuberculosisremains a major infectious disease worldwide. Moreover, latent M. tuberculosisinfection is more likely to progress to active TB and eventually leads to death when HIV infection is involved. Thus, it is urgent to develop a novel TB vaccine with immunogenicity to both M. tuberculosisand HIV. In this study, four uncharacterized T cell epitopes from MPT64, Ag85A, Ag85B, and TB10.4 antigens of M. tuberculosiswere predicted, and HIV-1-derived p24, an immunodominant protein that can induce protective responses to HIV-1, was used as an immunogenic backbone. M. tuberculosisepitopes were incorporated separately into the gene backbone of p24, forming a pP24-Mtb DNA vaccine. We demonstrated that pP24-Mtb immunization induced a strong M. tuberculosis-specific cellular response as evidenced by T cell proliferation, cytotoxicity, and elevated frequency of gamma interferon (IFN-?)-secreting T cells. Interestingly, a p24-specific cellular response and high levels of p24-specific IgG were also induced by pP24-Mtb immunization. When the protective effect was assessed after mycobacterial challenge, pP24-Mtb vaccination significantly reduced tissue bacterial loads and profoundly attenuated the mycobacterial infection-related lung inflammation and injury. Our findings demonstrated that the pP24-Mtb tuberculosis vaccine confers effective protection against mycobacterial challenge with simultaneously elicited robust immune responses to HIV-1, which may provide clues for developing novel vaccines to prevent dual infections.

C-reactive protein (CRP), an acute-phase protein with an ability to bind to nuclear antigen, has been reported to regulate cytokine secretion and modulate immune responses. We previously reported that activated syngeneic lymphocyte-derived apoptotic DNA (apopDNA) could induce macrophage activation and contribute to the initiation and progression of lupus nephritis. It is reasonable to hypothesize that CRP might regulate apopDNA-induced macrophage activation. Herein, CRP was shown to promote macrophage-mediated apopDNA uptake by binding to apopDNA (CRP/apopDNA complex). Notably, CRP/apopDNA treatment inhibited the production of inflammatory cytokines and chemokines by macrophages which could be induced by apopDNA alone. Further coculture and transwell studies revealed that CRP/apopDNA-induced macrophages prohibited apopDNA-induced macrophage activation in an IL-10 dependent manner. These results provide insight into the potential mechanism of CRP regulatory activity in macrophage activation induced by apopDNA in the context of lupus nephritis and other autoimmune diseases.

Adoptive cell transfer (ACT) immunotherapy administered with prior host immunosuppression significantly improved the anti-tumor efficacy in a murine model. However, bulk transfer of lymphocytes containing suppressor lymphocyte subsets, including regulatory T cells to mice bearing late-stage tumors impaired this anti-tumor effect. In this study, we investigated the enhanced anti-tumor efficacy by adoptive transfer of Treg-depleted autologous tumor infiltrating lymphocytes in advanced murine breast cancer. We found that, compared to bulk cell transfer, Treg-depleted cell transfer enhanced the activation and proliferation of both CD4+ and CD8+ T cells. Most importantly, the immune response deviated towards the Th1 response reflected by increased IFN-γand reduced IL-4 secretion in both CD4+ and CD8+ T cells and an enhanced granzyme B release of CTL. Furthermore, the elicited Th1 response subsequently resulted in delayed tumor growth and prolonged mice survival as well as reduced lung metastasis in tumor-bearing nude mice. These results strongly indicated that Treg-depleted autologous cell transfer greatly enhanced Th1 type immune response, consequently leading to delayed tumor growth and reduced tumor burden. Therefore, ACT immunotherapy based on ex vivo selection of tumor-reactive lymphocytes resulted in enhanced anti-tumor immunity and provides important implications for further human studies.

Although it is known that the chemoattractant effect of IFN‐γ inducible protein 10 (IP‐10), a CXC chemokine (CXCL10), plays an important role in T cell‐mediated antitumor immunity in vivo, whether IP‐10 is involved in modulating the proliferation, survival and functional activation of tumor‐specific T cells remains poorly investigated. Using an experimental mouse tumor model, we demonstrated that the in vivo growth of 4T1 tumor cells harboring IP‐10 gene (4T1‐IP‐10) was inhibited. Mice inoculated with 4T1‐IP‐10 tumor cells expressing functional IP‐10 survived over 90 days, whereas mice injected with control parental 4T1 cells and mice of control 4T1 cells transduced with control plasmid all succumbed to the tumor by day 38 after tumor inoculation. Mechanical analysis showed that targeted expression of IP‐10 in 4T1 tumor cells markedly enhanced the infiltration of tumor‐specific T cells into the 4T1‐IP‐10 tumor. These tumor infiltrating T lymphocytes (TILs) recruited by IP‐10 were potent cytolytic killers against 4T1 tumor cells and were able to proliferate and produce high levels of IFN‐γ in response to 4T1 cells. In vivo administration of IP‐10‐recruited TILs induced vigorous proliferation of these TILs in situ in the 4T1‐IP‐10 tumor but not in the 4T1‐pcDNA3 and parental 4T1 tumors. Furthermore, culture of TILs together with recombinant IP‐10 significantly enhanced the proliferation and expansion of IP‐10‐recruited TILs in response to 4T1 tumor antigens. These results suggest that IP‐10 is not only able to chemoattract tumor‐specific T cells into the local tissue, but also enhance the proliferation, survival, and functional activation of these TILs, leading to the tumor regression. Thus, targeted expression of IP‐10 in vivo will allow for the development of a novel approach for immunotherapy of tumor.

To investigate cyclin E, p16ink4a, and Ki67 as possible diagnostic biomarkers for cervical preneoplasia, and to evaluate its significance for screening human papillomavirus (HPV)-infected patients who are at high risk of developing cervical carcinoma.

A murine model of endotoxin-induced lethal liver injury induced by Mycobacterium bovis BCG plus lipopolysaccharide (LPS) has been widely accepted and used. It has been reported that T cells play an important role in the pathogenesis of liver damage in this model. However, the precise mechanisms involved in regulation of the trafficking of effector T cells need to be elucidated. In the present study, we first reported that CXCL16/SR-PSOX (CXC chemokine ligand 16/scavenger receptor that binds phosphatidylserine and oxidized lipoprotein), a chemokine containing both membrane-anchored and soluble forms, was strongly up-regulated and predominantly distributed in the vascular endothelium in the injured liver tissue in the model. The secretory and membrane-anchored CXCL16/SR-PSOX functioned as a chemokine and an adhesive molecule, respectively, to attract T cells to a tumor necrosis factor alpha-activated endothelial cell line (SVEC) in vitro. To further identify the pathophysiological roles of CXCL16/SR-PSOX in the liver injury, the anti-CXCL16 antibody was administered to the BCG-primed mice before LPS challenge in vivo. Significant protection effects were observed with 70% of mice regarding lethality, the massive necrosis in the liver was reduced, and the intrahepatic infiltrating T cells were significantly inhibited. Taken together, these findings strongly suggest that functional CXCL16/SR-PSOX, as both a chemokine and an adhesion molecule, may be involved in the pathogenesis of the endotoxin-induced lethal liver injury via recruitment and adhesion of activated T cells to the vascular endothelium.

ABSTRACTA murine model of endotoxin-induced lethal liver injury induced by Mycobacterium bovisBCG plus lipopolysaccharide (LPS) has been widely accepted and used. It has been reported that T cells play an important role in the pathogenesis of liver damage in this model. However, the precise mechanisms involved in regulation of the trafficking of effector T cells need to be elucidated. In the present study, we first reported that CXCL16/SR-PSOX (CXC chemokine ligand 16/scavenger receptor that binds phosphatidylserine and oxidized lipoprotein), a chemokine containing both membrane-anchored and soluble forms, was strongly up-regulated and predominantly distributed in the vascular endothelium in the injured liver tissue in the model. The secretory and membrane-anchored CXCL16/SR-PSOX functioned as a chemokine and an adhesive molecule, respectively, to attract T cells to a tumor necrosis factor alpha-activated endothelial cell line (SVEC) in vitro. To further identify the pathophysiological roles of CXCL16/SR-PSOX in the liver injury, the anti-CXCL16 antibody was administered to the BCG-primed mice before LPS challenge in vivo. Significant protection effects were observed with 70% of mice regarding lethality, the massive necrosis in the liver was reduced, and the intrahepatic infiltrating T cells were significantly inhibited. Taken together, these findings strongly suggest that functional CXCL16/SR-PSOX, as both a chemokine and an adhesion molecule, may be involved in the pathogenesis of the endotoxin-induced lethal liver injury via recruitment and adhesion of activated T cells to the vascular endothelium.

Recently, increasing attention is being paid to the viral etiology of atherosclerosis (AS). Human cytomegalovirus (HCMV) is thought to be the most possible etiological factor of AS. In our study, artery vascular tissue specimens derived from 75 patients with AS were studied for detection of HCMV immediately early (IE) and later (L) gene fragments by polymerase chain reaction (PCR) and in situhybridization; sera collected from the same patients were examined for HCMV specific IgG and IgM by enzyme-linked immunosorbent assay (ELISA). Twenty two normal arterial tissues and sera were used as controls. We found that the positive rate of HCMV L and IE gene fragments were significantly higher in AS patients than those in controls. HCMV DNA were mainly observed in nucleus of endothelial cells and muscularis under intima as well as smooth muscle of media of AS area, rarely found in controls. These results suggested that HCMV infection may relate to the pathogenesis of AS; and the artery itself may be the site of HCMV latency. In addition, higher levels of HCMV IgG and IgM were found to be associated with virus persistence, indicating that a periodically active latent infection or a continuously active infection is presented in AS patients.

We report on the induction of primary and long-term memory cytotoxic T 3;lymphocyte (CTL) responses against the nucleoprotein of the influenza virus A/PR8/34 in mice immunized with plasmid DNA targeted to B 3;lymphocytes in the spleen. We found that the magnitude of the CTL response and the size of the pool of memory CTL was greater when the CTL response was induced in presence of T 3;cell help. Interestingly, immunization with a signal sequence-competent transgene was markedly superior to immunization with a transgene lacking the endoplasmic reticulum (ER) targeting sequence, in inducing CTL. We also found a correlation between in vivo protection from lethal virus challenge and (1) the availability of T 3;cell help and (2) ER targeting. Immunization of dendritic cell-deficient mice suggests that B 3;lymphocytes function as antigen-presenting cells in this model of immunization. Collectively, the results suggest that somatic transgene immunization is a conceptually new approach to induce effective anti-viral CTL responses and to assess the parameters critical for long-lasting and protective CTL responses in vivo.

•MMP3 is upregulated in colon cancers.•Tumor cell-associated MMP3 expression is important for tumor growth.•The cancer therapy by MMP3 inhibition is improved together with oncolytic virus.•Downregulation of MMP3 reduces tumor cell invasion.•Erk1/2 and NF-κB signaling are changed by MMP3 downregulation.

Antibodies engineered in their variable domain to express epitopes of heterologous antigens—antigenized antibodies—function as immunogens. Only the third complementarity-determining region (CDR3) of the H chain has been used as the site of epitope expression, as this loop has the highest natural variability in length and amino acid composition. We demonstrate that the CDR2 can be engineered to express a 12–amino acid peptide, which is a T-cell determinant that enhances the response to a B-cell eprtope peptide of Plasmodium falciparum expressed in the CDR3 of the same variable domain. Mice with this gene inoculated into the spleen mounted an antibody response against the B-cell eprtope higher than mice receiving the gene coding for the B-cell eprtope only. In vitro studies established that the two epitopes were independently immunogenic in vivo.

It is unclear how the type I IFN response is regulated by mycobacterial determinants. Here, we characterized the previously unreported role of M. tuberculosisMmsA in immunological regulation of type I IFN response by targeting the central adaptor STING in the DNA sensing pathway. We identified STING-interacting MmsA by coimmunoprecipitation-mass spectrometry-based (IP-MS) proteomic analysis and showed MmsA interacting with STING and autophagy receptor p62 via its N terminus and C terminus, respectively. We also showed that MmsA downregulated type I IFN by promoting p62-mediated STING degradation. Moreover, the MmsA mutant R138W is potentially associated with the virulence of M. tuberculosisclinical strains owing to the modulation of STING protein. Our results provide novel insights into the regulatory mechanism of type I IFN response manipulated by mycobacterial MmsA and the additional cross talk between autophagy and STING in M. tuberculosisinfection, wherein a protein from microbial pathogens induces autophagic degradation of host innate immune molecules.