Biology subjects

Larson, H. N.

Publications and source records attributed to Larson, H. N..

4 recordsLinked to original sources

bioRxiv2026

Caspase-1 and -11 defend against environmental but not host-adapted pathogens in genetically complex mice

Caspase-1 and -11 are inflammatory caspases that trigger pyroptosis, yet in most infection models they confer only a modest survival benefit. We have proposed that caspase-1 and -11 evolved primarily to defend against ubiquitous environmental microbes that have not been under selective pressure to evade them, whereas host-adapted pathogens have evolved evasion strategies. Testing this idea is complicated because the inbred mouse strains used in most infection studies carry mutations in innate immune genes: i.e., C57BL/6 (B6) mice carry a loss-of-function Nramp1 allele, and 129 mice lack functional caspase-11. Here we generated B6 x 129 F1 hybrid mice, which are gene-sufficient at both Nramp1 and Casp11, and used them to measure the fold change in lethal dose ({triangleup}LD100) caused by caspase-1 and -11 deficiency for four pathogens on the B6, 129, and F1 backgrounds. Caspase-1 and -11 conferred little or no survival benefit against the host-adapted pathogens Listeria monocytogenes and Salmonella Typhimurium on any of the three backgrounds, apart from a modest benefit at the lowest S. Typhimurium inoculum in F1 mice. In contrast, caspase-1 and -11 were required to survive infection with the environmental pathogens Burkholderia thailandensis and Chromobacterium violaceum, where caspase-1 and -11 deficiency lowered the lethal dose by up to six orders of magnitude. The failure of caspase-1 and -11 against host-adapted pathogens therefore persists on a genetically robust hybrid background, supporting the view that a major evolutionary role of caspase-1 and -11 is defense against environmental microbes that have not been selected to evade them.

immunology↗

bioRxiv2026

Cytokines driven by caspase-1 and RIPK3 are antagonistic

Pyroptosis, apoptosis, and necroptosis are thought to provide redundant protection against intracellular pathogens. We found that mice lacking inflammasomes, caspase-8, and MLKL were highly susceptible to infection by an environmental cytosol-invasive bacterium. Surprisingly, deletion of Ripk3 completely restored resistance despite the continued absence of all three cell death pathways. The infection outcome was determined instead by the production of antagonistic cytokines arising from these pathways. Deletion of Casp8 and Mlkl initiated an effector-triggered immunity-like response, in which RIPK3 induced type I interferons causing catastrophic susceptibility by impeding neutrophil responses. Opposing this, caspase-1-dependent IL-1{beta} production counteracted these type I interferons and restored resistance. Thus, susceptibility arose not from failure of regulated cell death, but from the activation of RIPK3-driven type I interferons unopposed by caspase-1-driven IL-1{beta}. Therefore, antagonistic cytokines embedded within cell death pathway signaling, distinct from cell death itself, can dictate the immune response to intracellular infection.

immunology↗

bioRxiv2023

Apoptotic signaling clears engineered Salmonella in an organ-specific manner

Pyroptosis and apoptosis are two forms of regulated cell death that can defend against intracellular infection. Although pyroptosis and apoptosis have distinct signaling pathways, when a cell fails to complete pyroptosis, backup pathways will initiate apoptosis. Here, we investigated the utility of apoptosis compared to pyroptosis in defense against an intracellular bacterial infection. We previously engineered Salmonella enterica serovar Typhimurium to persistently express flagellin, and thereby activate NLRC4 during systemic infection in mice. The resulting pyroptosis clears this flagellin-engineered strain. We now show that infection of caspase-1 or gasdermin D deficient macrophages by this flagellin-engineered S. Typhimurium induces apoptosis in vitro. Additionally, we also now engineer S. Typhimurium to translocate the pro-apoptotic BH3 domain of BID, which also triggers apoptosis in macrophages in vitro. In both engineered strains, apoptosis occurred somewhat slower than pyroptosis. During mouse infection, the apoptotic pathway successfully cleared these engineered S. Typhimurium from the intestinal niche, but failed to clear the bacteria from the myeloid niche in the spleen or lymph nodes. In contrast, the pyroptotic pathway was beneficial in defense of both niches. In order to clear an infection, distinct cell types may have specific tasks that they must complete before they die. In some cells, either apoptotic or pyroptotic signaling may initiate the same tasks, whereas in other cell types these modes of cell death may lead to different tasks that may not be identical in defense against infection. We recently suggested that such diverse tasks can be considered as different cellular "bucket lists" to be accomplished before a cell dies.

immunology↗

bioRxiv2023

An innate granuloma eradicates an environmental pathogen using Gsdmd and Nos2

Granulomas often form around pathogens that cause chronic infections. Here, we discover a novel granuloma model in mice. Chromobacterium violaceum is an environmental bacterium that stimulates granuloma formation that not only successfully walls off but also clears the infection. The infected lesion can arise from a single bacterium that replicates in the presence of a neutrophil swarm. Bacterial replication ceases when macrophages organize around the infection and form a granuloma. This granuloma response is accomplished independently of adaptive immunity that is typically required to organize granulomas. The C. violaceum-induced granuloma requires at least two separate defense pathways, gasdermin D and iNOS, to maintain the integrity of the granuloma architecture. These innate granulomas successfully eradicate C. violaceum infection. Therefore, this new C. violaceum-induced granuloma model demonstrates that innate immune cells successfully organize a granuloma and thereby eradicate infection by an environmental pathogen.

immunology↗