Nicholas Arpaia

Publications (4)61.91 Total impact

• Article: The impact of Toll-like receptors on bacterial virulence strategies.

  Nicholas Arpaia, Gregory M Barton
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  ABSTRACT: The mammalian immune system has evolved in the presence of microbes, both pathogenic and commensal. The consequences of microbial recognition by the host has led to the development of compensatory mechanisms by both the host and microbe to either resist or tolerate the existence of the other. In this review we discuss examples of this co-evolutionary relationship. Because of space considerations and for conceptual clarity, we have focused on detection of bacteria by the Toll-like receptor (TLR) family and highlight examples of bacterial strategies to evade, subvert and in some cases even utilize these receptors.
  Current opinion in microbiology 01/2013; · 7.87 Impact Factor
• Article: Toll-like receptors: key players in antiviral immunity.

  Nicholas Arpaia, Gregory M Barton
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  ABSTRACT: TLRs are a family of innate receptors whose specificities are predetermined in the germline. Therefore, TLRs have evolved to recognize conserved features of microbes. Viruses typically lack the conserved features common to other pathogen classes, so the innate immune system has evolved to recognize viral nucleic acid as a hallmark of viral infection. In this review we discuss examples of TLR-mediated viral recognition and the functional consequences of this recognition for antiviral immunity.
  Current opinion in virology. 12/2011; 1(6):447-54.
• Article: Transmembrane mutations in Toll-like receptor 9 bypass the requirement for ectodomain proteolysis and induce fatal inflammation.

  Maria L Mouchess, Nicholas Arpaia, Gianne Souza, Roman Barbalat, Sarah E Ewald, Laura Lau, Gregory M Barton
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  ABSTRACT: Recognition of nucleic acids as a signature of infection by Toll-like receptors (TLRs) 7 and 9 exposes the host to potential self-recognition and autoimmunity. It has been proposed that intracellular compartmentalization is largely responsible for reliable self versus nonself discrimination by these receptors. We have previously shown that TLR9 and TLR7 require processing prior to activation, which may further reinforce receptor compartmentalization and tolerance to self, yet this possibility remains untested. Here we report that residues within the TLR9 transmembrane (TM) region conferred the requirement for ectodomain proteolysis. TLR9 TM mutants responded to extracellular DNA, and mice expressing such receptors died from systemic inflammation and anemia. This inflammatory disease did not require lymphocytes and appeared to require recognition of self-DNA by dendritic cells. To our knowledge, these results provide the first demonstration that TLR-intrinsic mutations can lead to a break in tolerance.
  Immunity 11/2011; 35(5):721-32. · 21.64 Impact Factor
• Source

  Available from: unicamp.br

  Article: TLR signaling is required for Salmonella typhimurium virulence.

  Nicholas Arpaia, Jernej Godec, Laura Lau, Kelsey E Sivick, Laura M McLaughlin, Marcus B Jones, Tatiana Dracheva, Scott N Peterson, Denise M Monack, Gregory M Barton
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  ABSTRACT: Toll-like receptors (TLRs) contribute to host resistance to microbial pathogens and can drive the evolution of virulence mechanisms. We have examined the relationship between host resistance and pathogen virulence using mice with a functional allele of the nramp-1 gene and lacking combinations of TLRs. Mice deficient in both TLR2 and TLR4 were highly susceptible to the intracellular bacterial pathogen Salmonella typhimurium, consistent with reduced innate immune function. However, mice lacking additional TLRs involved in S. typhimurium recognition were less susceptible to infection. In these TLR-deficient cells, bacteria failed to upregulate Salmonella pathogenicity island 2 (SPI-2) genes and did not form a replicative compartment. We demonstrate that TLR signaling enhances the rate of acidification of the Salmonella-containing phagosome, and inhibition of this acidification prevents SPI-2 induction. Our results indicate that S. typhimurium requires cues from the innate immune system to regulate virulence genes necessary for intracellular survival, growth, and systemic infection.
  Cell 03/2011; 144(5):675-88. · 32.40 Impact Factor