bims-inflin 2023-08-27 papers

Issue of 2023‒08‒27
five papers selected by
Juliane Cristina Ribeiro Fernandes, Faculdade de Medicina de Ribeirão Preto

Mol Microbiol. 2023 Aug 23.

Investigating pyroptosis as a mechanism of L. major cell-to-cell spread in the human BLaER1 infection model.

Kerren Volkmar, Moritz Jaedtka, Iris Baars, Bianca Walber, Marie-Sophie Philipp, Katrin Bagola, Andreas J Müller, Holger Heine, Ger van Zandbergen.

Leishmania is the causative agent of the tropical neglected disease leishmaniasis and infects macrophages as its definitive host cell. In order to sustain and propagate infections, Leishmania parasites have to complete cycles of exit and re-infection. Yet, the mechanism driving the parasite spread to other cells remains unclear. Recent studies reported pro-inflammatory monocytes as replicative niche of Leishmania major and showed prolonged expression of IL-1β at the site of infection, indicating an activation of the NLRP3 inflammasome and pointing toward pyroptosis as a possible mechanism of parasite spread. To address the species-specific inflammasome activation of human cells, we characterized the BLaER1 monocytes as a model for L. major infection. We found that BLaER1 monocytes support infection and activation by Leishmania parasites to the same extent as primary human macrophages. Harnessing the possibilities of this infection model, we first showed that BLaER1 GSDMD-/- cells, which carry a deletion of the pore-forming protein gasdermin D, are more resistant to pyroptotic cell death and, concomitantly, display a strongly delayed release of intracellular parasite. Using that knockout in a co-incubation assay in comparison with wild-type BLaER1 cells, we demonstrate that impairment of the pyroptosis pathway leads to lower rates of parasite spread to new host cells, thus, implicating pyroptotic cell death as a possible exit mechanism of L. major in pro-inflammatory microenvironments.

Keywords: BLaER1; Inflammasome; Leishmania; Parasite Exit; Pyroptosis

DOI: https://doi.org/10.1111/mmi.15142

Cells. 2023 Aug 17. pii: 2079. [Epub ahead of print]12(16):

Necrotic Cell Death and Inflammasome NLRP3 Activity in Mycobacterium bovis-Infected Bovine Macrophages.

Omar Escobar-Chavarría, Alejandro Benitez-Guzman, Itzel Jiménez-Vázquez, Jacobo Carrisoza-Urbina, Lourdes Arriaga-Pizano, Sara Huerta-Yépez, Guillermina Baay-Guzmán, José A Gutiérrez-Pabello.

Mycobacterium bovis is a facultative intracellular bacterium that produces cellular necrosis in granulomatous lesions in bovines. Although M. bovis-induced inflammation actively participates in granuloma development, its role in necrotic cell death and in bovine macrophages has not been fully explored. In this study, we evaluate the effect of M. bovis AN5 and its culture filtrate protein extract (CFPE) on inflammasome activation in bovine macrophages and its consequences on cell death. Our results show that both stimuli induce necrotic cell death starting 4 h after incubation. CFPE treatment and M. bovis infection also induce the maturation of IL-1β (>3000 pg/mL), oligomerization of ASC (apoptosis-associated speck-like protein containing CARD), and activation of caspase-1, following the canonical activation pathway of the NLRP3 inflammasome. Inhibiting the oligomerization of NLRP3 and caspase-1 decreases necrosis among the infected or CFPE-stimulated macrophages. Furthermore, histological lymph node sections of bovines naturally infected with M. bovis contained cleaved gasdermin D, mainly in macrophages and giant cells within the granulomas. Finally, the induction of cell death (apoptosis and pyroptosis) decreased the intracellular bacteria count in the infected bovine macrophages, suggesting that cell death helps to control the intracellular growth of the mycobacteria. Our results indicate that M. bovis induces pyroptosis-like cell death that is partially related to the NLRP3 inflammasome activation and that the cell death process could control bacterial growth.

Keywords: ASC specks; bovine tuberculosis; caspase-1; cell death pathways; inflammasome; pyroptosis

DOI: https://doi.org/10.3390/cells12162079

mBio. 2023 Aug 24. e0131023

Yersinia deploys type III-secreted effectors to evade caspase-4 inflammasome activation in human cells.

Jenna Zhang, Igor E Brodsky, Sunny Shin.

Yersinia are Gram-negative zoonotic bacteria that use a type III secretion system (T3SS) to inject Yersinia outer proteins into the host cytosol to subvert essential components of innate immune signaling. However, Yersinia virulence activities can elicit activation of inflammasomes, which lead to inflammatory cell death and cytokine release to contain infection. Yersinia activation and evasion of inflammasomes have been characterized in murine macrophages but remain poorly defined in human cells, particularly intestinal epithelial cells (IECs), a primary site of intestinal Yersinia infection. In contrast to murine macrophages, we find that in both human IECs and macrophages, Yersinia pseudotuberculosis T3SS effectors promote evasion of the caspase-4 inflammasome, which senses cytosolic lipopolysaccharide. The anti-phagocytic YopE and YopH, as well as the translocation regulator YopK, were collectively responsible for evading inflammasome activation, in part by inhibiting Yersinia internalization mediated by YadA and β1-integrin signaling. These data provide insight into the mechanisms of Yersinia-mediated inflammasome activation and evasion in human cells and reveal species-specific differences underlying the regulation of inflammasome responses to Yersinia. IMPORTANCE Yersinia are responsible for significant disease burden in humans, ranging from recurrent disease outbreaks (yersiniosis) to pandemics (Yersinia pestis plague). Together with rising antibiotic resistance rates, there is a critical need to better understand Yersinia pathogenesis and host immune mechanisms, as this information will aid in developing improved immunomodulatory therapeutics. Inflammasome responses in human cells are less studied relative to murine models of infection, though recent studies have uncovered key differences in inflammasome responses between mice and humans. Here, we dissect human intestinal epithelial cell and macrophage inflammasome responses to Yersinia pseudotuberculosis. Our findings provide insight into species- and cell type-specific differences in inflammasome responses to Yersinia.

Keywords: Yersinia; host-pathogen interactions; human innate immunity; inflammasome; intestinal epithelial cell; macrophages

DOI: https://doi.org/10.1128/mbio.01310-23

Int J Mol Sci. 2023 Aug 17. pii: 12871. [Epub ahead of print]24(16):

Deficiency of Caspase-1 Attenuates HIV-1-Associated Atherogenesis in Mice.

Mohammad Afaque Alam, Maurizio Caocci, Mi Ren, Zheng Chen, Fengming Liu, Mst Shamima Khatun, Jay K Kolls, Xuebin Qin, Tricia H Burdo.

Within arterial plaque, HIV infection creates a state of inflammation and immune activation, triggering NLRP3/caspase-1 inflammasome, tissue damage, and monocyte/macrophage infiltration. Previously, we documented that caspase-1 activation in myeloid cells was linked with HIV-associated atherosclerosis in mice and people with HIV. Here, we mechanistically examined the direct effect of caspase-1 on HIV-associated atherosclerosis. Caspase-1-deficient (Casp-1-/-) mice were crossed with HIV-1 transgenic (Tg26+/-) mice with an atherogenic ApoE-deficient (ApoE-/-) background to create global caspase-1-deficient mice (Tg26+/-/ApoE-/-/Casp-1-/-). Caspase-1-sufficient (Tg26+/-/ApoE-/-/Casp-1+/+) mice served as the controls. Next, we created chimeric hematopoietic cell-deficient mice by reconstituting irradiated ApoE-/- mice with bone marrow cells transplanted from Tg26+/-/ApoE-/-/Casp-1-/- (BMT Casp-1-/-) or Tg26+/-/ApoE-/-/Casp-1+/+ (BMT Casp-1+/+) mice. Global caspase-1 knockout in mice suppressed plaque deposition in the thoracic aorta, serum IL-18 levels, and ex vivo foam cell formation. The deficiency of caspase-1 in hematopoietic cells resulted in reduced atherosclerotic plaque burden in the whole aorta and aortic root, which was associated with reduced macrophage infiltration. Transcriptomic analyses of peripheral mononuclear cells and splenocytes indicated that caspase-1 deficiency inhibited caspase-1 pathway-related genes. These results document the critical atherogenic role of caspase-1 in chronic HIV infection and highlight the implication of this pathway and peripheral immune activation in HIV-associated atherosclerosis.

Keywords: HIV-1; animal models; atherosclerosis; caspase-1; macrophage

DOI: https://doi.org/10.3390/ijms241612871

Front Microbiol. 2023 ;14 1247377

Inflammasome activation by viral infection: mechanisms of activation and regulation.

Wen Shi, Mengyun Jin, Hao Chen, Zongxue Wu, Liuyang Yuan, Si Liang, Xiaohan Wang, Fareed Uddin Memon, Fatma Eldemery, Hongbin Si, Changbo Ou.

Viral diseases are the most common problems threatening human health, livestock, and poultry industries worldwide. Viral infection is a complex and competitive dynamic biological process between a virus and a host/target cell. During viral infection, inflammasomes play important roles in the host and confer defense mechanisms against the virus. Inflammasomes are polymeric protein complexes and are considered important components of the innate immune system. These immune factors recognize the signals of cell damage or pathogenic microbial infection after activation by the canonical pathway or non-canonical pathway and transmit signals to the immune system to initiate the inflammatory responses. However, some viruses inhibit the activation of the inflammasomes in order to replicate and proliferate in the host. In recent years, the role of inflammasome activation and/or inhibition during viral infection has been increasingly recognized. Therefore, in this review, we describe the biological properties of the inflammasome associated with viral infection, discuss the potential mechanisms that activate and/or inhibit NLRP1, NLRP3, and AIM2 inflammasomes by different viruses, and summarize the reciprocal regulatory effects of viral infection on the NLRP3 inflammasome in order to explore the relationship between viral infection and inflammasomes. This review will pave the way for future studies on the activation mechanisms of inflammasomes and provide novel insights for the development of antiviral therapies.

Keywords: Inflammasome; NLRP; inflammatory response; regulation; virus infection

DOI: https://doi.org/10.3389/fmicb.2023.1247377