Human genetics of meningococcal infections

Hodeib, Stephanie; Herberg, Jethro; Levin, Michael; Sancho-Shimizu, Vanessa

doi:10.1007/s00439-020-02128-4

Cited by 23 publications

(14 citation statements)

References 175 publications

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“…This is highlighted by clinical evidences showing that immunodeficiencies increasing the risk of IMD in humans are mostly innate immune deficiencies (i.e. defects in complement, defects in inflammatory response, or spleen dysfunction) [77,78]. The human skin-grafted SCID mice therefore represent a pertinent model, since these mice have all the key effectors of the innate immune response (inflammation, complement, phagocytes, NK cells).…”

Section: Plos Pathogensmentioning

confidence: 99%

Type IV pilus retraction enables sustained bacteremia and plays a key role in the outcome of meningococcal sepsis in a humanized mouse model

et al. 2021

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Neisseria meningitidis (the meningococcus) remains a major cause of bacterial meningitis and fatal sepsis. This commensal bacterium of the human nasopharynx can cause invasive diseases when it leaves its niche and reaches the bloodstream. Blood-borne meningococci have the ability to adhere to human endothelial cells and rapidly colonize microvessels. This crucial step enables dissemination into tissues and promotes deregulated inflammation and coagulation, leading to extensive necrotic purpura in the most severe cases. Adhesion to blood vessels relies on type IV pili (TFP). These long filamentous structures are highly dynamic as they can rapidly elongate and retract by the antagonistic action of two ATPases, PilF and PilT. However, the consequences of TFP dynamics on the pathophysiology and the outcome of meningococcal sepsis in vivo have been poorly studied. Here, we show that human graft microvessels are replicative niches for meningococci, that seed the bloodstream and promote sustained bacteremia and lethality in a humanized mouse model. Intriguingly, although pilus-retraction deficient N. meningitidis strain (ΔpilT) efficiently colonizes human graft tissue, this mutant did not promote sustained bacteremia nor induce mouse lethality. This effect was not due to a decreased inflammatory response, nor defects in bacterial clearance by the innate immune system. Rather, TFP-retraction was necessary to promote the release of TFP-dependent contacts between bacteria and, in turn, the detachment from colonized microvessels. The resulting sustained bacteremia was directly correlated with lethality. Altogether, these results demonstrate that pilus retraction plays a key role in the occurrence and outcome of meningococcal sepsis by supporting sustained bacteremia. These findings open new perspectives on the role of circulating bacteria in the pathological alterations leading to lethal sepsis.

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Section: Plos Pathogensmentioning

confidence: 99%

Type IV pilus retraction enables sustained bacteremia and plays a key role in the outcome of meningococcal sepsis in a humanized mouse model

et al. 2021

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“…Humans also have five FHR proteins; FHR-1, FHR-2, FHR-3, FHR-4 and FHR-5, whose functions are poorly characterized (described in more detail in ( 8 )). Yet, their importance is shown by the causal link between genetic alterations in CFHR and various diseases (i.e., IgA nephropathy (IgAN) ( 19 – 23 ), age-related macular degeneration (AMD) ( 24 – 28 ), invasive meningococcal disease ( 29 – 31 ), atypical hemolytic uremic syndrome (aHUS) ( 32 ) and C3 glomerulopathy (C3G) ( 33 ). All FHR proteins share a high degree of similarity with FH in their N-terminus (varying between 36 and 94%) and their C-terminus (varying between 36 and 100%) ( 34 ).…”

Section: Introduction: the Factor H Protein Familymentioning

confidence: 99%

A Family Affair: Addressing the Challenges of Factor H and the Related Proteins

et al. 2021

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Inflammation is a common denominator of diseases. The complement system, an intrinsic part of the innate immune system, is a key driver of inflammation in numerous disorders. Recently, a family of proteins has been suggested to be of vital importance in conditions characterized by complement dysregulation: the human Factor H (FH) family. This group of proteins consists of FH, Factor H-like protein 1 and five Factor H-related proteins. The FH family has been linked to infectious, vascular, eye, kidney and autoimmune diseases. In contrast to FH, the functions of the other highly homologous proteins are largely unknown and, hence, their role in the different disease-specific pathogenic mechanisms remains elusive. In this perspective review, we address the major challenges ahead in this emerging area, including 1) the controversies about the functional roles of the FH protein family, 2) the discrepancies in quantification of the FH protein family, 3) the unmet needs for validated tools and 4) limitations of animal models. Next, we also discuss the opportunities that exist for the immunology community. A strong multidisciplinary approach is required to solve these obstacles and is only possible through interdisciplinary collaboration between biologists, chemists, geneticists and physicians. We position this review in light of our own perspective, as principal investigators of the SciFiMed Consortium, a consortium aiming to create a comprehensive analytical system for the quantitative and functional assessment of the entire FH protein family.

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“…Monogenic infections are characterized by severe, unexplained infection with a single, common pathogen; the absence of classic immunological abnormalities; and a low penetrance. Vertical bars indicate healthy carriers of the deleterious genotype (see 2 decades later (21,135). These disorders did not usher in an era of research into the genetic basis of isolated infections, because their discovery did not follow the testing of the hypothesis that meningococcal disease could have a monogenic basis (8,21).…”

Section: Lessons From Mendelian Infectionsmentioning

confidence: 99%

Lethal Infectious Diseases as Inborn Errors of Immunity: Toward a Synthesis of the Germ and Genetic Theories

Casanova

Abel

2021

Annu. Rev. Pathol. Mech. Dis.

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It was first demonstrated in the late 19th century that human deaths from fever were typically due to infections. As the germ theory gained ground, it replaced the old, unproven theory that deaths from fever reflected a weak personal or even familial constitution. A new enigma emerged at the turn of the 20th century, when it became apparent that only a small proportion of infected individuals die from primary infections with almost any given microbe. Classical genetics studies gradually revealed that severe infectious diseases could be driven by human genetic predisposition. This idea gained ground with the support of molecular genetics, in three successive, overlapping steps. First, many rare inborn errors of immunity were shown, from 1985 onward, to underlie multiple, recurrent infections with Mendelian inheritance. Second, a handful of rare and familial infections also segregating as Mendelian traits but striking humans resistant to other infections were deciphered molecularly from 1996 onward. Third, a growing number of rare or common sporadic infections were shown to result from monogenic, but not Mendelian, inborn errors from 2007 onward. A synthesis of the hitherto mutually exclusive germ and genetic theories is now in view. This article has been accepted for publication on April 14, 2020. Changes may still occur before final publication. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 16 is January 24, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Human genetics of meningococcal infections

Cited by 23 publications

References 175 publications

Type IV pilus retraction enables sustained bacteremia and plays a key role in the outcome of meningococcal sepsis in a humanized mouse model

Type IV pilus retraction enables sustained bacteremia and plays a key role in the outcome of meningococcal sepsis in a humanized mouse model

A Family Affair: Addressing the Challenges of Factor H and the Related Proteins

Lethal Infectious Diseases as Inborn Errors of Immunity: Toward a Synthesis of the Germ and Genetic Theories

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