A Murine Mycobacterium marinum Infection Model for Longitudinal Analyses of Disease Development and the Inflammatory Response

Lienard, Julia; Munke, Kristina; Carlsson, Fredric

doi:10.1007/978-1-0716-3243-7_21

Cited by 3 publications

(1 citation statement)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While other bacteria have been found to establish infection of the tail, this trophism has not been previously reported in B. burgdorferi. 35,36 To ask whether B. burgdorferi were co-localized at the sites of atopic dermatitis, bacteria were imaged using an In Vivo Imaging System (IVIS) to visualize and quantify the bacterial load through the mice. The B. burgdorferi strain ML23-pBBE22luc (ML23) was used for infection, as it contains a luciferase plasmid reporter.…”

Section: In Vivo Tracking Of B Burgdorferi Localizes Into the Tailmentioning

confidence: 99%

Novel Association of Lyme disease, Age, and Atopic Dermatitis

Lee

Galloway

Strausz

et al. 2022

Preprint

View full text Add to dashboard Cite

Borrelia burgdorferi is a bacterial spirochete that can cause Lyme disease (LD) after infecting a susceptible host. Immune responses to the bacteria are highly variable and host specific. The murine substrain, C3H/HeJ, is a frequently utilized model for LD. Interestingly, we observed dermatitis with flaky lesions of the tail skin on C3H/HeJ after a year of infection with B. burgdorferi. Female C3H/HeJ mice aged 6-8 weeks, 1 year, or 2 years were infected intraperitoneally with 105 B. burgdorferi spirochetes. Mouse tails were evaluated by gross examination and histology either 2 months or 24 months post-infection. Dermatitis worsened over the course of untreated infection, with ulceration, hemorrhaging, flaking, hair loss, and dark lesions as well as spongiosis and acanthosis. These features of atopic dermatitis were present in infected mice after 1 year of age. This relationship among LD, atopic dermatitis, and host age seen in the C3H/HeJ mouse model is consistent with a large pool of human epidemiological data (342,499 individuals) from Finland. We identified 5,248 individuals with LD and 17,233 with atopic dermatitis in the FinnGen biobank. Retrospective analysis shows LD is associated with atopic dermatitis (OR = 1.91 [1.68 -2.37], P < 2e-16). Repeat visits for LD complications (3 or more visits versus 1 visit) were associated with atopic dermatitis (OR = 2.19 [1.35-3.55], P = 0.0014) and risk of developing atopic dermatitis over time (HR=2.26 [1.54-3.95] , P = 0.0017). Data from mice and humans reveal a novel relationship among LD, age, and atopic dermatitis. Through defined pathological scoring, we demonstrate that the onset of murine Lyme disease-associated atopic dermatitis is exacerbated by increased host age at time of B. burgdorferi infection. In humans, a diagnosis of Lyme disease in the FinnGen registry was associated with atopic dermatitis and further research is warranted to establish causation.

show abstract

Section: In Vivo Tracking Of B Burgdorferi Localizes Into the Tailmentioning

confidence: 99%

Novel Association of Lyme disease, Age, and Atopic Dermatitis

Lee

Galloway

Strausz

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

Cytosolic serpins act in a cytoprotective feedback loop that limits ESX-1-dependent death of Mycobacterium marinum -infected macrophages

Nobs,

Laschanzky,

Munke

et al. 2024

mBio

View full text Add to dashboard Cite

Serine protease inhibitors (serpins) constitute the largest family of protease inhibitors expressed in humans, but their role in infection remains largely unexplored. In infected macrophages, the mycobacterial ESX-1 type VII secretion system permeabilizes internal host membranes and causes leakage into the cytosol of host DNA, which induces type I interferon (IFN) production via the cyclic GMP-AMP synthase (cGAS) and stimulator of IFN genes (STING) surveillance pathway, and promotes infection in vivo . Using the Mycobacterium marinum infection model, we show that ESX-1-mediated type I IFN signaling in macrophages selectively induces the expression of serpina3f and serpina3g , two cytosolic serpins of the clade A3. The membranolytic activity of ESX-1 also caused leakage of cathepsin B into the cytosol where it promoted cell death, suggesting that the induction of type I IFN comes at the cost of lysosomal rupture and toxicity. However, the production of cytosolic serpins suppressed the protease activity of cathepsin B in this compartment and thus limited cell death, a function that was associated with increased bacterial growth in infected mice. These results suggest that cytosolic serpins act in a type I IFN-dependent cytoprotective feedback loop to counteract the inevitable toxic effect of ESX-1-mediated host membrane rupture. IMPORTANCE The ESX-1 type VII secretion system is a key virulence determinant of pathogenic mycobacteria. The ability to permeabilize host cell membranes is critical for several ESX-1-dependent virulence traits, including phagosomal escape and induction of the type I interferon (IFN) response. We find that it comes at the cost of lysosomal leakage and subsequent host cell death. However, our results suggest that ESX-1-mediated type I IFN signaling selectively upregulates serpina3f and serpina3g and that these cytosolic serpins limit cell death caused by cathepsin B that has leaked into the cytosol, a function that is associated with increased bacterial growth in vivo . The ability to rupture host membranes is widespread among bacterial pathogens, and it will be of interest to evaluate the role of cytosolic serpins and this type I IFN-dependent cytoprotective feedback loop in the context of human infection.

show abstract