30/08/2013

ESCMID Postgraduate Technical Workshop Intracellular : from biology to clinic Rickettsioses Villars-sur-Ollon, 26-30 August 2013

 Vary greatly from mild, self-limiting, -, louse and -borne to life-threatening diseases rickettsioses Mortality

0 % (R. slovaca, R. africae, R. felis)

Pierre-Edouard Fournier 1% (R. typhi)

Centre National de Référence des rickettsioses, 2 % (R. conorii, R. rickettsii) de la fièvre Q et des bartonelloses 20% (R. prowazekii)

U R

Virulence linked to genome reduction

Differences in pathogenicity

Role of genome decay on virulence?

 R. africae genome  1,27 Mb chromosome  1 unstable plasmid  Highly clonal  The most virulent species has the smallest genome

U  Loss of regulatory genes U © byR author R

ESCMIDAn isolated phenomenon?Online Lecture Library Species genome size (bp) GC (%) coding % ORFs pseudogenes phylum order/family M. leprae 3, 268, 203 57% 49% 1605 1115 Actinobacteria Mycobacteria M. avium 5, 475, 491 68% 88% 5120 1143 Actinobacteria Mycobacteria M. tuberculosis 4, 411, 532 65% 90% 3988 8 Actinobacteria Mycobacteria Differences in pathogenicity M. smegmatis 6, 988, 209 67% 90% 6716 168 Actinobacteria Mycobacteria R. prowazekii 1, 111, 523 29% 75% 835 0 Rickettsiae R. africae 1, 278, 540 32% 72% 1030 87 Proteobacteria Rickettsiae C. diphtheriae 2, 488, 635 53% 87% 2272 48 Actinobacteria Corynebacteria C. glutamicum 3, 314, 179 54% 86% 3052 0 Actinobacteria Corynebacteria T. pallidum 1, 139, 457 52% 93% 1028 9 Spirochetes Spirochaetaceae T. denticola 2, 843, 201 37% 91% 2767 19 Spirochetes Spirochaetaceae Y. pestis 4, 600, 755 47% 82% 4048 54 Proteobacteria γ-enterobacteria Y. pseudotuberculosis 4, 744, 671 47% 82% 3901 73 Proteobacteria γ-enterobacteria B. pertussis 4, 086, 189 67% 82% 3436 358 Proteobacteria β-enterobacteria B. bronchiseptica 5, 339, 179 68% 91% 4994 12 Proteobacteria β-enterobacteria S. pneumoniae 2, 078, 953 39% 85% 2115 0 Firmicutes Lactobacillales S. agalactiae 2, 160, 267 35% 86% 2124 0 Firmicutes Lactobacillales S. pyogenes 1, 852, 442 38% 83% 1696 35 Firmicutes Lactobacillales May differences among species S. suis 2, 096, 309 41% 86% 2186 0 Firmicutes Lactobacillales S. Typhi 4, 809, 037 52% 83% 4391 205 Proteobacteria γ-enterobacteria S. Schwarzengrund 4, 709, 075 52% 85% 4502 152 Proteobacteria γ-enterobacteria explain everything? S. dysenteriae 4, 369, 232 51% 76% 4270 284 Proteobacteria γ-enterobacteria E. coli HS 4, 643, 538 50% 86% 4378 95 Proteobacteria γ-enterobacteria V. cholerae chr1: 1, 108, 250 46% 86% 1133 0 Proteobacteria γ-enterobacteria chr2: 3, 024, 069 47% 88% 2742 1 Proteobacteria γ-enterobacteria

V .parahaemolyticus chr1: 3, 288, 558 45% 86% 3080 0 Proteobacteria γ-enterobacteria chr2: 1, 877, 212 45% 86% 1752 0 Proteobacteria γ-enterobacteria

U U R R

1 30/08/2013

Worse outcome

Pathogenesis of rickettsial infections  Age > 40 years (RMSF), > 60 years (MSF)

 Male sex (! occupational bias)

 Ethnical factors: Native Americans (reduced access to healthcare facilities)

Host-associated factors  Comorbidities: Chronic alcoholism, diabetes

 Genetic background: deficit in G6PD

mutated TLR-4

U U R R

Worse outcome

Pathogenesis of rickettsial infections  Delayed diagnosis and treatment

 Cotrimoxazole, chloramphenicol in MSF and ET

Impact of treatment

 Fluoroquinolones in ET, MT, MSF

U U © byR author R

ESCMIDFew answers, Onlinemany questions Lecture Library  Pathogenesis only partially known  Virulence of rickettsiae is multi-parametric  Adhesion to host cells crucial (SCA proteins) Flea-transmitted  Host factors play a significant role rickettsioses  Comparative genomics may help identify virulence factors  Role of T4SS?  Role of toxin-antitoxin modules? Worldwide diseases

U U R R

2 30/08/2013

Flea-transmitted diseases

 R. felis  R. typhi  B. henselae  B. quintana?  Y. p e s t i s

U U R R

Murine Fleas  typhi (R. mooseri)  Vector : rat fleas (X. cheopis), fleas, mouse fleas  Reservoir: rats, , opossums  Infection by flea feces  Prevalent in southern USA, Hawai, central and south America, Africa, Asia (Indonesia), Mediterranean area (Greece, Cyprus, Spain, North Africa)  Fever, headache, arthro-myalgias, MP rash (40 - 50 %)  Neurological signs such as confusion, stupor, seizures or imbalance (up to 45%)  Mostly mild. Deadly in elderly and immunocompromised U U © byR authorpatients without treatment R

Flea ESCMID Online Lecture Triad fever + eschar + rash = “Yaaf”Library in Africa (febrile Flea spotted fever vesicular rash with eschar) Mediannikov et al. J Infect . 2013;66:536-40  Photophobia, hearing loss, and signs of meningitis (rare)

 Mostly mild  In 1970, changing distribution of  USA, Brazil, Mexico,  Cases in the rich Orange county (CA) Germany, France,  Opossums = major actors Australia, Algeria  Infested by cat fleas (C. felis)  Fever (100%), MP or vesicular rash  High seroprevalence in Senegal (90%), eschar (variable depending on and Kenya (51 and 57% of febrile patients, respectively) Maina et al. Emerg Infect Dis. 2012;18:328-31 country)

(Raoult et al. Emerg Infect Dis. 2001) (similar U  Role of and mosquitoes in Africa U R epidemiology to malaria) Socolovschi et al. PLOS One. 2012;7:e48254 R

3 30/08/2013

Louse transmitted bacteria

Louse-transmitted  rickettsioses  Borrelia recurrentis  quintana

 Acinetobacter baumanii?

U R

Human lice Pediculus humanus humanus -transmitted bacteria

Russia France R. prowazekii B. quintana B. quintana

Algeria R. prowazekii USA B. quintana Sudan Peru B. recurrentis R. prowazekii B. quintana Burundi Pediculus humanus capitis Pediculus humanus humanus Phtirus pubis B. quintana Zimbabwe R. prowazekii B. quintana

U © byR author(Fournier et al. Emerg Infect Dis 2002)

Blood meal on a healthy ESCMIDPediculus humanus Online humanus Lecture Library volunteer  P.h.humanus only bites humans (except Culpepper)  Only blood meal  5 meals/d  Highly sensitive to heat and dessication

U U R R

4 30/08/2013

P.h. humanus lives , In clothes Reemerging disease

 1990-1992: Isolated cases in Ethiopia and Nigeria (Perine et al. Clin. Infect. Dis. 1992)  1990-1993: Isolated cases in Peru (WHO memorandum. Bull. World Health Organ. 1993)  1993 : Civil war in Burundi and Rwanda  1994 : 800,000 Rwandan refugees in Goma, Zaïre  Louse outbreak but no typhus  1995: outbreak in a jail in Burundi: 9 cases (Raoult et al. Emerg. Infect. Dis. 1997)  1996-1997: Outbreak in refugee camps in Burundi > 45,000 cas (Raoult et al. Lancet. 1998) U U R  2004: Isolated case in Algeria (Mokrani et al. J. Clin. Microbiol. 2004) R

Epidemic typhus Epidemic typhus in USA (Jail fever, Red louse fever) Role of flying squirrels (1975)

 Rickettsia prowazekii (Houhamidi et al. J. Infect. Dis. 2002)  Vector : only P. h. humanus (not capitis)  R. prowazekii associated to squirrel lice  Fever - rash : 30 - 60 %  East and West USA  Myalgia ++ (“sutama”)  Less severe  Headache, obnubilation (“tuphos”)  10-30% mortality without treatment  Treatment : unique dose of 200 mg doxycycline

U U © byR author R

ESCMIDDetection of R. Onlineprowazekii Lecture Library in

Mite-transmitted 1966: Amblyomma in Africa Reiss-Gutfreund RJ. 1966. Am J Trop Med Hyg; 15: 943-49. rickettsioses 2005: Amblyomma in Mexico in 2005 Medina-Sanchez A., et al. 2005. Ann N Y Acad Sci; 1063:327-32.

Role in epidemiology?

U U R R

5 30/08/2013

Rickettsialpox

 Vector = Allodermanyssus sanguineus (mouse mite) Didier Raoult  Prevalent in USA, Ukraine,, Jean-Paul Casalta Slovenia, Korea  Fever, rash (vesicular) Gilbert Habib Eschar, regional lymph nodes  Mild Franck Thuny  New York +++  High seroprevalence in Frédéric Collart Baltimore drug addicts  Under high surveillance since 9-11, Hubert Lepidi 2001 (eschar ~ smallpox) (Paddock et al. Ann N Y Acad Sci. 2003) U U R THANK YOU ! R

© by author ESCMID Online Lecture Library

6