Tobacco Upregulates P. gingivalis Fimbrial Proteins Which Induce TLR2 Hyposensitivity

Tobacco smokers are more susceptible to periodontitis than non-smokers but exhibit reduced signs of clinical inflammation. The underlying mechanisms are unknown. We have previously shown that cigarette smoke extract (CSE) represents an environmental stress to which P. gingivalis adapts by altering the expression of several virulence factors - including major and minor fimbrial antigens (FimA and Mfa1, respectively) and capsule - concomitant with a reduced pro-inflammatory potential of intact P. gingivalis.We hypothesized that CSE-regulation of capsule and fimbrial genes is reflected at the ultrastructural and functional levels, alters the nature of host-pathogen interactions, and contributes to the reduced pro- inflammatory potential of smoke exposed P. gingivalis. CSE induced ultrastructural alterations were determined by electron microscopy, confirmed by Western blot and physiological consequences studied in open-flow biofilms. Inflammatory profiling of specific CSE-dysregulated proteins, rFimA and rMfa1, was determined by quantifying cytokine induction in primary human innate and OBA-9 cells. CSE up-regulates P. gingivalis FimA at the protein level, suppresses the production of capsular polysaccharides at the ultrastructural level, and creates conditions that promote biofilm formation. We further show that while FimA is recognized by TLR2/6, it has only minimal inflammatory activity in several cell types. Furthermore, FimA stimulation chronically abrogates the pro-inflammatory response to subsequent TLR2 stimulation by other TLR-2-specific agonists (Pam3CSK4, FSL, Mfa1) in an IkappaBalpha- and IRAK-1-dependent manner.These studies provide some of the first information to explain, mechanistically, how tobacco smoke changes the P. gingivalis phenotype in a manner likely to promote P. gingivalis colonization and infection while simultaneously reducing the host response to this major mucosal pathogen

A Novel Mouse Model of <i>Schistosoma haematobium</i> Egg-Induced Immunopathology

<div><p><i>Schistosoma haematobium</i> is the etiologic agent for urogenital schistosomiasis, a major source of morbidity and mortality for more than 112 million people worldwide. Infection with <i>S. haematobium</i> results in a variety of immunopathologic sequelae caused by parasite oviposition within the urinary tract, which drives inflammation, hematuria, fibrosis, bladder dysfunction, and increased susceptibility to urothelial carcinoma. While humans readily develop urogenital schistosomiasis, the lack of an experimentally-tractable model has greatly impaired our understanding of the mechanisms that underlie this important disease. We have developed an improved mouse model of <i>S. haematobium</i> urinary tract infection that recapitulates several aspects of human urogenital schistosomiasis. Following microinjection of purified <i>S. haematobium</i> eggs into the bladder wall, mice consistently develop macrophage-rich granulomata that persist for at least 3 months and pass eggs in their urine. Importantly, egg-injected mice also develop urinary tract fibrosis, bladder dysfunction, and various urothelial changes morphologically reminiscent of human urogenital schistosomiasis. As expected, <i>S. haematobium</i> egg-induced immune responses in the immediate microenvironment, draining lymph nodes, and systemic circulation are associated with a Type 2-dominant inflammatory response, characterized by high levels of interleukin-4, eosinophils, and IgE. Taken together, our novel mouse model may help facilitate a better understanding of the unique pathophysiological mechanisms of epithelial dysfunction, tissue fibrosis, and oncogenesis associated with urogenital schistosomiasis.</p></div

The immune response to infection in the bladder

International audienceThe bladder is continuously protected by passive defences such as a mucus layer, antimicrobial peptides and secretory immunoglobulins; however, these defences are occasionally overcome by invading bacteria that can induce a strong host inflammatory response in the bladder. The urothelium and resident immune cells produce additional defence molecules, cytokines and chemokines, which recruit inflammatory cells to the infected tissue. Resident and recruited immune cells act together to eradicate bacteria from the bladder and to develop lasting immune memory against infection. However, urinary tract infection (UTI) is commonly recurrent, suggesting that the induction of a memory response in the bladder is inadequate to prevent reinfection. Additionally, infection seems to induce long-lasting changes in the urothelium, which can render the tissue more susceptible to future infection. The innate immune response is well-studied in the field of UTI, but considerably less is known about how adaptive immunity develops and how repair mechanisms restore bladder homeostasis following infection. Furthermore, data demonstrate that sex-based differences in immunity affect resolution and infection can lead to tissue remodelling in the bladder following resolution of UTI. To combat the rise in antimicrobial resistance, innovative therapeutic approaches to bladder infection are currently in development. Improving our understanding of how the bladder responds to infection will support the development of improved treatments for UTI, particularly for those at risk of recurrent infection