Anaplasma phagocytophilum AptA modulates Erk1/2 signalling

Sukumaran, Bindu; Mastronunzio, Juliana E.; Narasimhan, Sukanya; Fankhauser, Sarah C.; Uchil, Pradeep D.; Levy, Roie; Graham, Morven; Colpitts, Tonya M.; Lesser, Cammie F.; Fikrig, Erol

doi:10.1111/j.1462-5822.2010.01516.x

Cited by 45 publications

(52 citation statements)

References 67 publications

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“…We detected expression of 27 hypothetical proteins in tick salivary glands by proteomics or RNA-seq (Table 3 and Table 4). Some of these proteins have previously been characterized in HL-60 cultures for their roles in A. phagocytophilum infection (14,15,34) or identified as immunoreactive proteins (24). Two hypothetical proteins, APH_0220 and APH_0792, were classified as among the most abundant in the HL-60 culture proteome (23).…”

Section: Resultsmentioning

confidence: 99%

Postgenomic Analyses Reveal Development of Infectious Anaplasma phagocytophilum during Transmission from Ticks to Mice

2012

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Obligate intracellular bacteria of the Rickettsiales order have evolved to colonize both arthropod and mammalian hosts, but few details are known about the bacterial adaptations that occur during transmission from blood-feeding arthropods to mammals. Here we apply proteomics and transcriptome sequencing to Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis, in Ixodes scapularis tick salivary glands, to detect proteins or genes expressed by the pathogen during transmission feeding by the tick. We detected expression of 139 genes, representing 11% of the open reading frames (ORFs) in the A. phagocytophilum genome. The predominant categories of proteins were ribosomal proteins, cell surface proteins, chaperones, and uncharacterized proteins. There was no evidence of DNA replication enzymes, suggesting that most of the A. phagocytophilum cells were no longer dividing. Instead, protein expression reflected conversion to the extracellular, infectious "dense-core" (DC) form. High expression of a DC-specific marker, APH_1235, further suggested this developmental transition in ticks. We showed that blocking APH_1235 with antibodies reduced A. phagocytophilum infection levels in mammalian cell culture. This work represents a starting point for clarifying essential proteins expressed by A. phagocytophilum during transmission from ticks to mammals and demonstrates that the abundantly expressed, DC-associated APH_1235 protein is important during in vivo infection by A. phagocytophilum.

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Section: Resultsmentioning

confidence: 99%

Postgenomic Analyses Reveal Development of Infectious Anaplasma phagocytophilum during Transmission from Ticks to Mice

2012

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“…The ectopic expression of the A. phagocytophilum AptA protein activates ERK1/2 in HL-60 cells (Fig. 4) (210). AptA interacts with the intermediate filament protein vimentin, which is essential for A. phagocytophilum-induced ERK1/2 activation and infection (210).…”

Section: Other Host Cell Signals Activated and Required Formentioning

confidence: 99%

“…(132). Several hypothetical proteins in A. phagocytophilum were found to be surface-exposed proteins, inclusion membrane proteins, and T4S substrates that confer unique phenotypes to this bacterium (74,99,100,166,195,210). A. phagocytophilum and Rickettsia prowazekii share 469 genes (61), and both bacteria cannot use glucose as a carbon or energy source.…”

Section: Genomic Featuresmentioning

confidence: 99%

Mechanisms of Obligatory Intracellular Infection with Anaplasma phagocytophilum

2011

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SUMMARY Anaplasma phagocytophilum persists in nature by cycling between mammals and ticks. Human infection by the bite of an infected tick leads to a potentially fatal emerging disease called human granulocytic anaplasmosis. A. phagocytophilum is an obligatory intracellular bacterium that replicates inside mammalian granulocytes and the salivary gland and midgut cells of ticks. A. phagocytophilum evolved the remarkable ability to hijack the regulatory system of host cells. A. phagocytophilum alters vesicular traffic to create an intracellular membrane-bound compartment that allows replication in seclusion from lysosomes. The bacterium downregulates or actively inhibits a number of innate immune responses of mammalian host cells, and it upregulates cellular cholesterol uptake to acquire cholesterol for survival. It also upregulates several genes critical for the infection of ticks, and it prolongs tick survival at freezing temperatures. Several host factors that exacerbate infection have been identified, including interleukin-8 (IL-8) and cholesterol. Host factors that overcome infection include IL-12 and gamma interferon (IFN-γ). Two bacterial type IV secretion effectors and several bacterial proteins that associate with inclusion membranes have been identified. An understanding of the molecular mechanisms underlying A. phagocytophilum infection will foster the development of creative ideas to prevent or treat this emerging tick-borne disease.

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“…Rifampicin and the new fluoroquinolone antibiotic trovafloxacin are effective in vitro (Horowitz et al, 2001;Klein et al, 1997), but limited in vivo studies are available to confirm the in vitro data (Buitrago et al, 1998;Krause et al, 2003) A. phagocytophilum resides and proliferates in the professional killer cells of the host and disrupts many cell functions, in particular by modulating host-cell signalling to benefit itself and establish infection in the host (Rikihisa, 2003(Rikihisa, , 2006. It has been shown that A. phagocytophilum activates extracellular signal-regulated kinase (ERK) in neutrophils and HL-60 cells (Lee et al, 2008;Sukumaran et al, 2011;Xiong et al, 2009) and that ERK activation is required for A. phagocytophilum infection (Xiong et al, 2009). One of the best-characterized ERK activation pathways is Ras/Raf/MEK/ ERK (Roux & Blenis, 2004), and manumycin A, a farnesyltransferase inhibitor, is known to inhibit this pathway by inhibiting Ras farnesylation (Ito et al, 1996).…”

Section: Introductionmentioning

confidence: 66%

“…Therefore, A. phagocytophilum infection may activate ERK in an alternative pathway. Recently, an A. phagocytophilum virulence protein, AptA, was identified as being involved in the activation of ERK1/2 during A. phagocytophilum infection (Sukumaran et al, 2011).…”

Section: Discussionmentioning

confidence: 99%