pathogenesis of rickettsial diseases -...
TRANSCRIPT
Pathogenesis of Rickettsial Pathogenesis of Rickettsial DiseasesDiseases
DAVID H. WALKER, M.D.DAVID H. WALKER, M.D.The The CarmageCarmage and Martha Walls Distinguished Chair in Tropical Diseasesand Martha Walls Distinguished Chair in Tropical Diseases
Professor and Chairman, Department of PathologyProfessor and Chairman, Department of PathologyExecutive Director,Executive Director,
Center for Center for BiodefenseBiodefense and Emerging Infectious Diseaseand Emerging Infectious DiseaseUniversity of Texas Medical BranchUniversity of Texas Medical Branch
Rickettsial Spotted Fevers, Etiologic Agents, and Geographic Distribution
USA, Russia, USA, Russia, Croatia, TurkeyCroatia, Turkey
R. R. akariakariRickettsialpoxRickettsialpox
Europe, Africa, AsiaEurope, Africa, AsiaR. conoriiR. conoriiBoutonneuse feverBoutonneuse fever
North and South North and South AmericaAmerica
R. parkeriR. parkeriAmerican tick bite American tick bite feverfever
Africa, West IndiesAfrica, West IndiesR. africaeR. africaeAfrican tick bite African tick bite feverfever
The AmericasThe AmericasRickettsia Rickettsia rickettsiirickettsii
Rocky Mountain Rocky Mountain spotted feverspotted fever
Geographic Geographic DistributionDistribution
Etiologic Etiologic AgentAgent
DiseaseDisease
Rickettsial Spotted Fevers, Etiologic Agents, and Geographic Distribution
Japan, KoreaJapan, KoreaR. japonicaR. japonicaJapanese spotted feverJapanese spotted feverAustralia, Southeast Australia, Southeast AsiaAsia
R. R. honeihoneiFlinders Island spotted Flinders Island spotted feverfever
Presumably Presumably worldwideworldwide
R. felisR. felisFlea borne spotted Flea borne spotted feverfever
EuropeEuropeR. R. slovacaslovacaTick borne Tick borne lymphadenopathylymphadenopathy
Northern AsiaNorthern AsiaRickettsia Rickettsia sibiricasibirica
North Asian tick North Asian tick typhustyphus
Eastern AustraliaEastern AustraliaR. R. australisaustralisQueensland tick Queensland tick typhustyphus
Geographic Geographic DistributionDistribution
Etiologic AgentEtiologic AgentDiseaseDisease
Rocky Mountain spotted fever United States, 1920 - 2004
Comparison of Rickettsia rickettsii Infections in Brazil and US
4.4% of cases in 4.4% of cases in household with another household with another casecaseCase fatality rate Case fatality rate ∼∼4% 4% (23% pre(23% pre--antibiotic era)antibiotic era)Median fatal course: 11 Median fatal course: 11 days (preantibiotic era) days (preantibiotic era) Pathology seldom shows Pathology seldom shows significant hemorrhage significant hemorrhage (scattered petechiae)(scattered petechiae)
Frequently large clusters Frequently large clusters of casesof cases∼∼ 50%50%∼∼6 days (currently) 6 days (currently) Fatal cases are Fatal cases are frequently a severe frequently a severe hemorrhagic fever.hemorrhagic fever.
USUS BrazilBrazil
1001008888Fever (%)Fever (%)72729595Eschar (%)Eschar (%)005454Multiple eschars (%)Multiple eschars (%)
NANA5151Regional Regional lymphadenopathy (%)lymphadenopathy (%)
R. R. conoriiconorii
R. R. africaeafricae
Agent
Signs and Symptoms of African Tick Bite Signs and Symptoms of African Tick Bite Fever and Boutonneuse FeverFever and Boutonneuse Fever
97974646Rash (%)Rash (%)90905151maculopapular (%)maculopapular (%)101044purpuricpurpuric (%)(%)004545vesicular (%)vesicular (%)2200Deaths (%)Deaths (%)
R. R. conoriiconorii
R. R. africaeafricae
Agent
Signs and Symptoms of African Tick Bite Signs and Symptoms of African Tick Bite Fever and Boutonneuse FeverFever and Boutonneuse Fever
Buea
Muyuka
Tiko
Limbe Douala
Gulf of Guinea
Estuary ofCameroon
DoualaYAOUNDÉ
9º 30`
4°
Study sites of Study sites of African tick bite African tick bite fever in Cameroonfever in Cameroon
African Tick Bite Fever among Africans
Among 234 patients in whom malaria or Among 234 patients in whom malaria or typhoid fever was suspected and ruled typhoid fever was suspected and ruled out, 32% had out, 32% had IgMIgM antibodies to antibodies to Rickettsia africaeRickettsia africae (IFA titers 32 to 2,048).(IFA titers 32 to 2,048).
African Tick Bite Fever among AfricansComparison of Comparison of R. conoriiR. conorii titers and titers and R. R. africaeafricae OmpAOmpA and and OmpBOmpB immunoblotting immunoblotting showed that at least 26 of 75 patients had showed that at least 26 of 75 patients had African tick bite fever. None were African tick bite fever. None were documented to have documented to have R. conoriiR. conorii infections.infections.In a subsequent study, 7 patients were In a subsequent study, 7 patients were diagnosed by real time PCR to have diagnosed by real time PCR to have R. R. africaeafricae infection (fever, 7; headache, 5; infection (fever, 7; headache, 5; myalgia and/or arthralgia 6; rash, 1; myalgia and/or arthralgia 6; rash, 1; pulmonary signs, 2). pulmonary signs, 2).
Documented Human Case of Rickettsia parkeri Infection in USPapules Papules →→ pustules pustules →→ ulcers ulcers →→escharsescharsFever, headache, malaise, Fever, headache, malaise, myalgias/arthalgiasmyalgias/arthalgiasMaculopapular rashMaculopapular rashLymphadenopathyLymphadenopathy
Documented Human Case of Rickettsia parkeri Infection in USEschar biopsy: Eschar biopsy: lymphohistocyticlymphohistocyticvaculitisvaculitis, immunohistochemical detection , immunohistochemical detection of SFG rickettsiaeof SFG rickettsiaeIsolation and PCR identification of Isolation and PCR identification of R. R. parkeriparkeriSerum antibody titer of 2048 to Serum antibody titer of 2048 to R. parkeriR. parkeriby IFAby IFA
Ecology of Tick-Bite Feverin the Western Hemisphere
Arthropod HostArthropod Host--Amblyomma maculatum, A. americanum, A. triste, A. cooperi, A. variegatum ticks
Established Geographic DistributionEstablished Geographic Distribution--U.S., Brazil, Uruguay, French West IndiesU.S., Brazil, Uruguay, French West Indies
AgentAgent-- R. parkeri/R. parkeri/R.africaeR.africae
Uruguayan Tick-bite FeverFever 100%Tender lymphadenopathy 100%Eschar 100%Maculopapular rash 20-50%
Some cases confirmed by IFA for antibodies to SFG rickettsiaeAssociated with R. parkeri-infected Amblyommatriste tick bite
Rev Med Uruguay 17:2; 119-124, 2001
Percentage of Mexican Patients with Different SignsPercentage of Mexican Patients with Different Signsand Symptoms Compared According to the Serologicaland Symptoms Compared According to the Serological
Evidence of SFG Rickettsiosis and Dengue FeverEvidence of SFG Rickettsiosis and Dengue Fever
575770Eye pain405660Chills27a6985aRash336333Nausea676985Headache909495Myalgia9794100Fever
Neither(n=30)
Dengue(n=16)
SFG Rickettsiosis
(n=20)
Symptoms and Signs
Percentage of Mexican Patients with Different SignsPercentage of Mexican Patients with Different Signsand Symptoms Compared According to the Serologicaland Symptoms Compared According to the Serological
Evidence of SFG Rickettsiosis and Dengue FeverEvidence of SFG Rickettsiosis and Dengue Fever
333135Photophobia1038b5bVomiting27615Cough72515Abdominal
pain10610Petechiae365Epistaxis
Neither(n=30)
Dengue(n=16)
SFG Rickettsiosis
(n=20)
Symptoms and Signs
Clinical Manifestations of Clinical Manifestations of Rickettsia Rickettsia felisfelis Infection in Four Patients in the Infection in Four Patients in the State of YucatState of Yucatáán, Mexicon, Mexico
NRNR++00++Abdominal Abdominal painpain
NRNR++00++MyalgiaMyalgia
NRNR++++NRNRFatigueFatigue
NRNR++++NRNRHeadacheHeadache
++++NRNR++FeverFever
++++++++ExanthemExanthem
44332211
Ecology of Flea-borne Spotted Fever
Arthropod HostArthropod Host--Maintained Maintained transovariallytransovariallyin in Ctenocephalides felis
fleas
Established Geographic DistributionEstablished Geographic Distribution--U.S., Mexico, Brazil, Peru, Europe, U.S., Mexico, Brazil, Peru, Europe, Africa, Asia, presumably worldwideAfrica, Asia, presumably worldwide
AgentAgent-- R. felisR. felis
World Distribution of LouseWorld Distribution of Louse--borne borne Typhus Fever at the End of World WarTyphus Fever at the End of World War IIII
Recrudescent TyphusRecrudescent Typhus
Latent human infection with R. prowazekii for years after primary typhus
Waning immunitytheoretically becauseof poor nutrition, age,alcohol, stress, or otherfactors Reactivation of
R. prowazekiiinfection
Rickettsemia
Human body louseacquires R. prowazekiifrom human bloodAfter 5-7 days,
infectious R. prowazekiiare present in the louse feces
Louse leaves febrile patient
Rickettsiae grow inlouse midgutepithelial cells
Locations of Recent Louse-borne Typhus
EthiopiaEthiopia
FranceFrance
PeruPeru
RussiaRussia
AlgeriaAlgeria
CongoCongo
RwandaRwanda
BurundiBurundi
Enormous Epidemic of Louse-borne Typhus during Civil War in Burundi
Outbreaks in louseOutbreaks in louse--infected jail infected jail populations with high incidence and populations with high incidence and 15% case15% case--fatality rate (1995) fatality rate (1995) Diagnosis of typhus in fatal disease of a Diagnosis of typhus in fatal disease of a repatriated Swiss nurse suspected to be repatriated Swiss nurse suspected to be a viral hemorrhagic fever provided a a viral hemorrhagic fever provided a delayed alertdelayed alert
Enormous Epidemic of Louse-borne Typhus during Civil War in Burundi
100,000 cases of typhus in refugee 100,000 cases of typhus in refugee campscampsDoxycycline treatment (March 1997) Doxycycline treatment (March 1997) and and permethrinpermethrin louse control louse control (August 1997) (August 1997)
Dolan PG and Carter DC. Mammalian Species 78:1Dolan PG and Carter DC. Mammalian Species 78:1--6, 19776, 1977
Distribution of Distribution of GlaucomysGlaucomys volansvolans
Contemporary Flying Squirrel-associated Typhus in the U.S.
Fever 100%Headache 81%Maculopapular rash 66%Confusion 44%Myalgia 42%Case fatality ratio 0%
Dengue Syndrome in Mexico
Among 394 suspected cases of dengue fever, 25.1% had antibodies to typhus group rickettsiae
Isolation and genetic and antigenic identification of Rickettsia prowazekii in cayenne ticks in Nuevo Leon
Amblyomma cajennense
Geographic Distribution of Murine TyphusGeographic Distribution of Murine Typhus
Ecology of Murine Typhus
Rickettsial Genomes in DecayRickettsial Genomes in DecayThe coding sequences of most bacterial The coding sequences of most bacterial genomes range from 87 to 94%;genomes range from 87 to 94%;The coding sequences of rickettsial genomes The coding sequences of rickettsial genomes range from 76 to 81%;range from 76 to 81%;229 intact genes of 229 intact genes of R. conoriiR. conorii that have that have remnant sequences in remnant sequences in R. prowazekiiR. prowazekiiR. typhiR. typhi has the most has the most pseudogenespseudogenes (41). (41). Genomes of TG rickettsiae have decayed Genomes of TG rickettsiae have decayed fasterfaster than SFG rickettsiaethan SFG rickettsiae
ConclusionsConclusionsLoss of genes for sugar metabolism, lipid Loss of genes for sugar metabolism, lipid biosynthesis, nucleotide synthesis, and biosynthesis, nucleotide synthesis, and amino acid synthesis may explain failure amino acid synthesis may explain failure of cultivationof cultivationStrong genetic similarities of the genomes Strong genetic similarities of the genomes suggest that our seemingly endless suggest that our seemingly endless creation of new species should terminatecreation of new species should terminate
Rickettsial Genes Effecting PathogenesisRickettsial Genes Effecting PathogenesisAdhesins: Adhesins: ompAompA, , ompBompBPhagosomal escape: Phagosomal escape: pldpld, , tlyCtlyCActinActin--based mobility: based mobility: rickArickAOther potential membranolytic activity: Other potential membranolytic activity: tlyAtlyA, pat, pat--11AutotransportersAutotransporters: OmpA, : OmpA, OmpBOmpB and and ScaSca proteinsproteinsType IV secretion system: Type IV secretion system: virB/virDvirB/virD genesgenesinvAinvA and others suchand others such sodBsodB and and IpxLIpxL
Rickettsial Propulsion by Host FRickettsial Propulsion by Host F--actinactin
Rickettsia conoriiRickettsia conorii Infection of MicrocirculationInfection of Microcirculation
Pathogenic Mechanisms of Cell and Tissue Injury in Rocky Mountain Spotted Fever
Production of reactive oxygen species by Production of reactive oxygen species by rickettsiarickettsia--infected endothelial cells infected endothelial cells →→oxidative stressoxidative stressHost factors: older age, Host factors: older age, glucoseglucose--66--phosphate phosphate dehydrogenasedehydrogenase deficiencydeficiency(? oxidative stress(? oxidative stress--inducedinducedhemolysishemolysis), ), sulfonanidesulfonanidetreatment (? oxidative stress),treatment (? oxidative stress),diabetes, male genderdiabetes, male gender
Cerebral Perivascular Edema in Cerebral Perivascular Edema in Rickettsial EncephalitisRickettsial Encephalitis
Rickettsial Vasculitis: the Host Defense Components
Cytokine-activated NO-dependent Rickettsial Killing by Autophagy
Phagolysosomal Rickettsial Death
Relative Susceptibility of Normal C57BL/6,Relative Susceptibility of Normal C57BL/6,IFNIFN--γγ Gene Knockout, and MHC Class I GeneGene Knockout, and MHC Class I Gene
Knockout Mice to Knockout Mice to Rickettsia australisRickettsia australis
0.50.5MHC MHC –– I KOI KO3131PerforinPerforin KOKO1.95 x 101.95 x 1022IFNIFN-- γ γ KOKO
3.6 x 103.6 x 1044WildWild--type C57BL/6type C57BL/6
LDLD5050Mouse strainMouse strain
Differential Diagnosis of Rickettsial Infections
Early stage: dengue, typhoid fever, malaria, drug reaction, hepatitis, secondary syphilis, measles, rubella, enteroviral and other arboviral infections
Severe stage: meningococcemia, staphylococcal bacteremia, toxic shock syndrome, leptospirosis, viral hemorrhagic fever, thrombotic thrombocytopenic purpura
Differential Diagnosis of Rickettsial Infections
Prominent gastrointestinal symptoms:viral or bacterial enterocolitis, acute surgical abdomen
Prominent neurologic signs: viral or bacterial meningoencephalitis
Prominent pulmonary signs: pneumonia, ARDS
Why Rickettsial Diseases Are Neglected and Seldom DiagnosedDiagnostic assays are rarely available in the tropicsDiagnostic assays are rarely available in the tropicsSingle sample acute serologic diagnosis is Single sample acute serologic diagnosis is insensitiveinsensitiveLack of epidemiologic data (incidence, geographic Lack of epidemiologic data (incidence, geographic distribution, seasonality) in most tropical locations distribution, seasonality) in most tropical locations bury rickettsioses among malaria, typhoid, acute bury rickettsioses among malaria, typhoid, acute viral syndrome, FUO considerationsviral syndrome, FUO considerationsPaucity of clinical studies that address rickettsioses Paucity of clinical studies that address rickettsioses in tropicsin tropics
Opportunities
Absence of established centers of excellence for Absence of established centers of excellence for the study of rickettsioses in the tropics.the study of rickettsioses in the tropics.Growing cadre of well trained Growing cadre of well trained rickettsiologistsrickettsiologistsin South America and Africa.in South America and Africa.Regions with sufficiently high incidence to Regions with sufficiently high incidence to investigate prospectively mechanisms of investigate prospectively mechanisms of human immunity, host risk factors for severity human immunity, host risk factors for severity of illness, basic science of diverse interesting of illness, basic science of diverse interesting rickettsial strains, and vector biologyrickettsial strains, and vector biology