Type I Interferon Induction Is Detrimental during Infection with the Whipple's Disease Bacterium, Tropheryma whipplei

Abstract Background The Type I interferon response is an important first-line defense against viruses. In turn, viruses antagonize (i.e., degrade, mis-localize, etc.) many proteins in interferon pathways. Thus, hosts and viruses are locked in an evolutionary arms race for dominance of the Type I interferon pathway. As a result, many genes in interferon pathways have experienced positive natural selection in favor of new allelic forms that can better recognize viruses or escape viral antagonists. Here, we performed a holistic analysis of selective pressures acting on genes in the Type I interferon family. We initially hypothesized that the genes responsible for inducing the production of interferon would be antagonized more heavily by viruses than genes that are turned on as a result of interferon. Our logic was that viruses would have greater effect if they worked upstream of the production of interferon molecules because, once interferon is produced, hundreds of interferon-stimulated proteins would activate and the virus would need to counteract them one-by-one. Results We curated multiple sequence alignments of primate orthologs for 131 genes active in interferon production and signaling (herein, “induction” genes), 100 interferon-stimulated genes, and 100 randomly chosen genes. We analyzed each multiple sequence alignment for the signatures of recurrent positive selection. Counter to our hypothesis, we found the interferon-stimulated genes, and not interferon induction genes, are evolving significantly more rapidly than a random set of genes. Interferon induction genes evolve in a way that is indistinguishable from a matched set of random genes (22% and 18% of genes bear signatures of positive selection, respectively). In contrast, interferon-stimulated genes evolve differently, with 33% of genes evolving under positive selection and containing a significantly higher fraction of codons that have experienced selection for recurrent replacement of the encoded amino acid. Conclusion Viruses may antagonize individual products of the interferon response more often than trying to neutralize the system altogether.

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Tropheryma whipplei, Immunosuppression and Whipple's Disease: From a Low-Pathogenic, Environmental Infectious Organism to a Rare, Multifaceted Inflammatory Complex

Digestive Diseases ◽

10.1159/000369538 ◽

2015 ◽

Vol 33 (2) ◽

pp. 190-199 ◽

Cited By ~ 10

Author(s):

Thomas Marth

Keyword(s):

Heart Valves ◽

Clinical Manifestations ◽

Systemic Infection ◽

Tropheryma Whipplei ◽

Molecular Techniques ◽

Whipple’S Disease ◽

Whipple's Disease ◽

New Findings ◽

The Central Nervous System ◽

Body Compartments

Background: The actinobacterium Tropheryma whipplei was detected 20 years ago by molecular techniques, and following its culture has been characterized as the cause of a systemic infection known as Whipple's disease (WD). T. whipplei occurs in the environment, is prevalent only in humans, is believed to be transmitted via oral routes and to be host dependent. Key Messages: The classical form of T. whipplei infection, i.e. classical WD (CWD), is rare. It is well defined as slowly progressing chronic infection with arthralgia, diarrhea and weight loss, mostly in middle-aged men. However, current research revealed a much broader spectrum of clinical features associated with T. whipplei infection. Thus, T. whipplei may cause acute and transient infections (observed primarily in children) and the bacterium, which is found in soil and water, occurs in asymptomatic carriers as well as in CWD patients in clinical remission. In addition, T. whipplei affects isolated and localized body compartments such as heart valves or the central nervous system. Subtle immune defects and HLA associations have been described. New findings indicate that the progression of asymptomatic T. whipplei infection to clinical WD may be associated with medical immunosuppression and with immunomodulatory conditions. This explains that there is a discrepancy between the widespread occurrence of T. whipplei and the rareness of WD, and that T. whipplei infection triggered by immunosuppression presents with protean clinical manifestations. Conclusions: This review highlights recent findings and the clinical spectrum of infection with T. whipplei and WD, focusing specifically on the role of host immunity and immunosuppression. Current concepts of the pathogenesis, diagnosis and therapy are discussed.

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Tropheryma whipplei, the Whipple's disease bacillus, induces macrophage apoptosis through the extrinsic pathway

Cell Death and Disease ◽

10.1038/cddis.2010.11 ◽

2010 ◽

Vol 1 (4) ◽

pp. e34-e34 ◽

Cited By ~ 21

Author(s):

L Gorvel ◽

K Al Moussawi ◽

E Ghigo ◽

C Capo ◽

J-L Mege ◽

...

Keyword(s):

Tropheryma Whipplei ◽

Whipple’S Disease ◽

Extrinsic Pathway ◽

Whipple's Disease ◽

Macrophage Apoptosis

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Obesity worsens the outcome of influenza virus infection associated with impaired type I interferon induction in mice

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2019.03.211 ◽

2019 ◽

Vol 513 (2) ◽

pp. 405-411 ◽

Cited By ~ 4

Author(s):

Ho Namkoong ◽

Makoto Ishii ◽

Hideki Fujii ◽

Takahiro Asami ◽

Kazuma Yagi ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Type I Interferon ◽

Influenza Virus Infection ◽

Type I ◽

Interferon Induction

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Tropheryma whippleiCrystalline Keratopathy: Report of a Case and Updated Review of the Literature

Case Reports in Ophthalmological Medicine ◽

10.1155/2012/707898 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Scott D. Schoenberger ◽

Sumeer Thinda ◽

Stephen J. Kim

Keyword(s):

Signs And Symptoms ◽

Tropheryma Whipplei ◽

Extensive Literature ◽

Whipple’S Disease ◽

Whipple's Disease ◽

Case Presentation ◽

Search Terms ◽

Crystalline Keratopathy ◽

Extensive Literature Search ◽

English Articles

Purpose. To report a case ofTropheryma whippleiinfection with crystalline keratopathy and review the recent literature on the presentation, diagnosis, and management of Whipple's disease.Methods. Detailed case presentation and extensive literature search of Pubmed for all years through February 2012 using the following search terms:Whipple's disease, Tropheryma whipplei, corneal deposits, crystalline keratopathy, and uveitis. Relevant articles were retrieved and analyzed. English abstracts were used for non-English articles. Cross-referencing was employed and reference lists from selected articles were used to identify additional pertinent articles.Results. Diagnosis of Whipple's disease remains challenging and untreated infection can result in mortality. Ocular signs and symptoms are usually nonspecific, but several independent cases have reported the presence of intraocular crystals or crystalline-like deposits.Conclusions. The presence of intraocular crystals or crystalline-like deposits may be an identifying feature of ocular Whipple’s disease.

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