An Ancient Molecular Arms Race: Chlamydia vs. Membrane Attack Complex/Perforin (MACPF) Domain Proteins

Keb, Gabrielle; Fields, Kenneth A.

doi:10.3389/fimmu.2020.01490

Cited by 5 publications

(5 citation statements)

References 85 publications

(127 reference statements)

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“…In the course of co-evolution with the host, chlamydiae have acquired their own MACPF-domain protein. It is assumed that this has enabled chlamydial organisms to partially resist MACPF effector mechanisms from the host and to facilitate their own infection [44]. The orthologous MACPF-domain protein of C. trachomatis was suggested to be able to permeabilize the inclusion membrane [45].…”

Section: Genomic Regions Of Lowermentioning

confidence: 99%

Extensive genomic divergence among 61 strains ofChlamydia psittaci

Sachse

Hölzer

Vorimore

et al. 2022

Preprint

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Chlamydia (C.) psittaci, the causative agent of avian chlamydiosis and human psittacosis, is a genetically heterogeneous species. Its broad host range includes parrots and many other birds, but occasionally also humans (via zoonotic transmission), ruminants, horses, swine and rodents. To assess whether there are genetic markers associated with host tropism we comparatively analyzed whole-genome sequences of 61 C. psittaci strains. Initially, poorly assembled genomes in public databases were subjected to clean-up, reassembly and polishing. Multiple sequence alignment of the genome sequences revealed four major clades within this species. Clade 1 represents the most recent lineage comprising 40/61 strains and contains 9/10 of the psittacine strains, including type strain 6BC, and 10/13 of human isolates. Clades 2-4 carry strains from different non-psittacine hosts. We found that clade membership correlates with classification schemes based on SNP types, ompA genotypes, multilocus sequence types as well as plasticity zone (PZ) structure and host preference. Genome analysis also revealed that i) sequence variation in the major outer membrane porin OmpA can result in 3D structural changes of immunogenic domains, ii) past host change of Clade 3 and 4 strains could be associated with loss of MAC/perforin in the PZ, rather than the large cytotoxin, iii) the distinct phylogeny of atypical strains (Clades 3 and 4) is also reflected in their repertoire of inclusion proteins (Inc family) and polymorphic membrane proteins (Pmps). Altogether, our study identified a number of genomic features that can be correlated with the phylogeny and host preference of C. psittaci strains.

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Section: Genomic Regions Of Lowermentioning

confidence: 99%

Extensive genomic divergence among 61 strains ofChlamydia psittaci

Sachse

Hölzer

Vorimore

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…In the course of co-evolution with the host, chlamydiae have acquired their own MACPF-domain protein. It is assumed that this has enabled chlamydial organisms to partially resist MACPF effector mechanisms from the host and to facilitate their own infection [ 57 ]. The orthologous MACPF-domain protein of C. trachomatis was suggested to be able to permeabilize the inclusion membrane [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

Genomic analysis of 61 Chlamydia psittaci strains reveals extensive divergence associated with host preference

et al. 2023

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Background Chlamydia (C.) psittaci, the causative agent of avian chlamydiosis and human psittacosis, is a genetically heterogeneous species. Its broad host range includes parrots and many other birds, but occasionally also humans (via zoonotic transmission), ruminants, horses, swine and rodents. To assess whether there are genetic markers associated with host tropism we comparatively analyzed whole-genome sequences of 61 C. psittaci strains, 47 of which carrying a 7.6-kbp plasmid. Results Following clean-up, reassembly and polishing of poorly assembled genomes from public databases, phylogenetic analyses using C. psittaci whole-genome sequence alignment revealed four major clades within this species. Clade 1 represents the most recent lineage comprising 40/61 strains and contains 9/10 of the psittacine strains, including type strain 6BC, and 10/13 of human isolates. Strains from different non-psittacine hosts clustered in Clades 2– 4. We found that clade membership correlates with typing schemes based on SNP types, ompA genotypes, multilocus sequence types as well as plasticity zone (PZ) structure and host preference. Genome analysis also revealed that i) sequence variation in the major outer membrane porin MOMP can result in 3D structural changes of immunogenic domains, ii) past host change of Clade 3 and 4 strains could be associated with loss of MAC/perforin in the PZ, rather than the large cytotoxin, iii) the distinct phylogeny of atypical strains (Clades 3 and 4) is also reflected in their repertoire of inclusion proteins (Inc family) and polymorphic membrane proteins (Pmps). Conclusions Our study identified a number of genomic features that can be correlated with the phylogeny and host preference of C. psittaci strains. Our data show that intra-species genomic divergence is associated with past host change and includes deletions in the plasticity zone, structural variations in immunogenic domains and distinct repertoires of virulence factors.

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“…Because phagocytes limit chlamydiae infections, investigators evaluated the role of Perforin-2 in an intravaginal infection model with Chlamydia muridarum ; a gram-negative, obligate intracellular pathogen ( 73 , 74 ). In addition, cell based assays had previously established that Perforin-2 limits the growth of chlamydiae in macrophages ( 72 ).…”

Section: Animal Models For Perforin-2 Researchmentioning

confidence: 99%

“…In addition, cell based assays had previously established that Perforin-2 limits the growth of chlamydiae in macrophages ( 72 ). In the intravaginal model Mpeg1 −/− mice exhibited significantly greater weight loss than wild-type controls and displayed other signs of morbidity such as ruffled fur ( 74 ). Surprisingly, there was no difference in the time to resolution — as determined by shedding of inclusion forming units, a quantitative indicator of infectivity and/or transmissibility—between the two groups.…”

Section: Animal Models For Perforin-2 Researchmentioning

confidence: 99%

“…However, the researchers also observed that Perforin-2 deficient mice shed less inclusion forming units; especially, at mid-time points of the infection. To explain this conundrum the researchers speculate that C. muridarum may more easily ascend the genital tract and disseminate in Perforin-2 deficient than wild-type mice ( 74 ). However the experiment was not designed to test that hypothesis.…”

Section: Animal Models For Perforin-2 Researchmentioning

confidence: 99%

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Breaching the Bacterial Envelope: The Pivotal Role of Perforin-2 (MPEG1) Within Phagocytes

2021

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The membrane attack complex (MAC) of the complement system and Perforin-1 are well characterized innate immune effectors. MAC is composed of C9 and other complement proteins that target the envelope of gram-negative bacteria. Perforin-1 is deployed when killer lymphocytes degranulate to destroy virally infected or cancerous cells. These molecules polymerize with MAC-perforin/cholesterol-dependent cytolysin (MACPF/CDC) domains of each monomer deploying amphipathic β-strands to form pores through target lipid bilayers. In this review we discuss one of the most recently discovered members of this family; Perforin-2, the product of the Mpeg1 gene. Since their initial description more than 100 years ago, innumerable studies have made macrophages and other phagocytes some of the best understood cells of the immune system. Yet remarkably it was only recently revealed that Perforin-2 underpins a pivotal function of phagocytes; the destruction of phagocytosed microbes. Several studies have established that phagocytosed bacteria persist and in some cases flourish within phagocytes that lack Perforin-2. When challenged with either gram-negative or gram-positive pathogens Mpeg1 knockout mice succumb to infectious doses that the majority of wild-type mice survive. As expected by their immunocompromised phenotype, bacterial pathogens replicate and disseminate to deeper tissues of Mpeg1 knockout mice. Thus, this evolutionarily ancient gene endows phagocytes with potent bactericidal capability across taxa spanning sponges to humans. The recently elucidated structures of mammalian Perforin-2 reveal it to be a homopolymer that depends upon low pH, such as within phagosomes, to transition to its membrane-spanning pore conformation. Clinical manifestations of Mpeg1 missense mutations further highlight the pivotal role of Perforin-2 within phagocytes. Controversies and gaps within the field of Perforin-2 research are also discussed as well as animal models that may be used to resolve the outstanding issues. Our review concludes with a discussion of bacterial counter measures against Perforin-2.

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An Ancient Molecular Arms Race: Chlamydia vs. Membrane Attack Complex/Perforin (MACPF) Domain Proteins

Cited by 5 publications

References 85 publications

Extensive genomic divergence among 61 strains ofChlamydia psittaci

Extensive genomic divergence among 61 strains ofChlamydia psittaci

Genomic analysis of 61 Chlamydia psittaci strains reveals extensive divergence associated with host preference

Breaching the Bacterial Envelope: The Pivotal Role of Perforin-2 (MPEG1) Within Phagocytes

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