ReviewHost-Pathogen Interactions

Targeting of host cell receptor tyrosine kinases by intracellular pathogens

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Science Signaling  17 Sep 2019:
Vol. 12, Issue 599, eaau9894
DOI: 10.1126/scisignal.aau9894

Figures

  • Fig. 1 RTKs and downstream signaling elements hijacked by intracellular pathogens.

    The interaction of some intracellular pathogens with RTKs or RTK-interacting receptors at the host cell surface is critical for the pathogens to enter the cells. Whereas some pathogens interact with RTKs directly, others do so through adaptor proteins. These interactions may trigger pathogen entry independently of receptor kinase activity or mediate the activation of RTKs, which results in signaling to downstream components that enable entry. Some intracellular pathogens also target RTK-mediated signaling events necessary for proper trafficking of the pathogen or for suppressing innate immune responses during the early stages of infection.

    CREDIT: A. KITTERMAN/SCIENCE SIGNALING
  • Fig. 2 Interactions of viruses with RTKs and mechanisms triggered by these interactions.

    The interaction of viruses with RTKs, directly or through adaptors such as Gas6, triggers several mechanisms that facilitate entry, including receptor clustering in lipid rafts, lateral movement of viral particles to sites of internalization near tight junctions, clathrin-mediated endocytosis, and actin cytoskeleton dynamics. AcMAPV, autographica californica multicapsid nucleopolyhedrovirus; AMAV, Amapari virus; CVB, coxsackievirus B; CHIKV, chikungunya virus; DENV, dengue virus; EEEV, eastern equine encephalitis virus; HCMV, human cytomegalovirus; HCV, hepatitis C virus; HIV-1, human immunodeficiency virus 1; HPV, human papillomavirus; HSV-1, herpes simplex virus type 1; IAV, influenza A virus; KSHV, Kaposi’s sarcoma-associated herpesvirus; LCMV, lymphocytic choriomeningitis virus; MARV, Marburg virus; NiV, Nipah virus; PICV, Pichinde virus; RRV, Rose River virus; SINV, Sindbis virus; SV40, simian virus 40; TCRV, Tacaribe virus; TGEV, porcine transmissible gastroenteritis virus; VACV, vaccinia virus; VSV, vesiculovirus; WNV, West Nile virus; YFV, yellow fever virus; ZIKV, Zika virus; CAR, coxsackievirus and adenovirus receptor; EBOV (Ebola virus); LASV (Lassa virus).

    CREDIT: A. KITTERMAN/SCIENCE SIGNALING
  • Fig. 3 Interactions of prokaryotic and eukaryotic microorganisms with RTKs.

    Several intracellular bacterial pathogens target RTKs for entry into the host cell. These bacteria stimulate signaling pathways to control actin cytoskeleton dynamics that mediate their entry into the host cell. C. trachomatis can bind to FGFRs indirectly through its interaction with FGF2. C. pneumoniae, Salmonella, and Listeria bind directly to RTKs through the bacterial cell surface proteins Pmp21, Rck, and InlB, respectively. Listeria can also interact with host cells after it has been packaged and secreted from infected macrophages within host cell membrane–derived vesicles that have exposed phosphatidylserine (PS). It is possible that the PS on these vesicles interacts with TAM through Gas6. Cbl, casitas B-lineage lymphoma.

    CREDIT: A. KITTERMAN/SCIENCE SIGNALING

Tables

  • Table 1 RTKs that mediate pathogen entry.

    AAV2 and AAV3, adeno-associated viruses 2 and 3; AcMAPV, autographica californica multicapsid nucleopolyhedrovirus; AMAV, Amapari virus; CHIKV, chikungunya virus; DENV, dengue virus; EBOV, Ebola virus; EEEV, eastern equine encephalitis virus; HCMV, human cytomegalovirus; HCV, hepatitis C virus; HPV, human papillomavirus; IAV, influenza A virus; HSV-1, herpes simplex virus 1; JEV, Japanese encephalitis virus; KSHV, Kaposi’s sarcoma-associated herpesvirus; LASV, Lassa virus; LCMV, lymphocytic choriomeningitis virus; MARV, Marburg virus; PICV, Pichinde virus; RRV, Rose River virus; RSV, respiratory syncytial virus; SARSV, severe acute respiratory syndrome virus; SINV, Sindbis virus; SV40, simian virus 40; TCRV, Tacaribe virus; TGEV, porcine transmissible gastroenteritis virus; PRRSV, porcine reproductive and respiratory syndrome virus; VACV, vaccinia virus; VSV, vesicular stomatitis virus; WNV, West Nile virus; YFV, yellow fever virus; ZIKV, Zika virus.

    KinasePathogen classPathogen speciesMode of interactionsKinase activity required?References
    AxlVirusCHIKV, RRV, EEEV, SINV,
    AMAV, LASV, lentivirus, PICV,
    LCMV, TCRV, EBOV, MARV,
    AcMAPV, DENV, ZIKV, WNV,
    YFV, VACV, VSV, SV40
    Indirect: Gas6DENV: No
    ZIKV: Yes
    All other viruses: ?
    (1517)
    Tyro3VirusDENVIndirect: Gas6?(20)
    ZIKV?Yes(16, 17)
    SV40Direct?(15)
    FGFRVirusAAV2 and AAV3?No(94)
    IAV?Yes(95)
    HPV?Yes(96)
    BacteriaChlamydia trachomatisIndirect: FGF2Yes(39, 97)
    EphA2VirusKSHV, HCVDirectKSHV: Yes
    HCV: ?
    (46, 98)
    BacteriaChlamydia trachomatisDirectYes(97)
    EGFRVirusHCMVDirectYes(33, 34, 99)
    HCV, HPV, IAV, RSV, SARSV?Yes(32)
    EBOV?Yes(100)
    LASV?Yes(100)
    PRRSVIndirect: Syndecan-4Yes(101)
    TGEV?Yes(57)
    JEV?Yes(66)
    HSV-1?Yes(58)
    BacteriaCampylobacter jejuni,
    Shigella flexneri
    ?Yes(32, 102)
    Salmonella typhimuriumDirectYes(72)
    Chlamydia pneumoniaeDirectYes(32, 97)
    FungiCandida albicansDirectYes(103)
    Her2 (ErbB2)BacteriaM. lepraeDirectYes(32)
    N. meningitidis?Yes(32)
    FungiCandida albicans (Als1 and
    Ssa1 proteins)
    DirectYes(103)
    PDGFRVirusHCMVDirectYes(34)
    IAV??(104)
    BacteriaChlamydia trachomatisDirectYes(39, 97)
    Campylobacter Jejuni?Yes(32)
    c-MetVirusAAV2Direct?(94)
    IAV?Yes(56)
    EBOV?Yes(105)
    BacteriaL. monocytogenes (InlB)DirectYes(106)
    ProtistPlasmodium berghei
    sporozoites
    NoYes(55)
    TrkCProtistTrypanosoma cruziDirectYes(107)
  • Table 2 RTKs that mediate entry of pathogens and some of their chemical inhibitors.

    RTKInhibitorReferences
    FGFRPD173074(39)
    PDGFRAG1296(39)
    EGFRErlotinib, sunitinib(32)
    EphA2Dasatinib(46)
    HGFR (c-Met)EMD-1214063(105)
    AXL (TAM)BGB324 (R428),
    BMS-777607
    (16, 77)
    Her2 (ErbB2)AG825(103)
    TrkCK252a, AG879(107)

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