INFECCIONES POR CITOMEGALOVIRUS

Presentación del tema: "INFECCIONES POR CITOMEGALOVIRUS"— Transcripción de la presentación:

1 INFECCIONES POR CITOMEGALOVIRUS
Dr. Jorge A. Lemus Arias Médico Residente Medicina Interna SEPTIEMBRE 2012

2 INTRODUCCIÓN Afecta pacientes de todas las edades.
Infección latente en pacientes inmunocompetentes. Infección silenciosa. Afección en feto. Miembro de la familia herpesvirus.

3 ANTECEDENTES 1881 Ribbert observó células grandes en riñón y glándula parótida de un recién nacido con sífilis. Lowenstein encontró 4 casos en 30 infantes. 1925 Von Gahn y Pappenheimer encontraron inclusiones intranucleares en hombres con herpes. casos más. Wyatt propone “enfermedad de inclusión citomegálica generalizada”. 1953 Minders observó por microscopio electrónico partículas 199 nm en células pancreáticas. 1955 Margareth Smith aisló el virus. 1957 se aisló virus de un niño con sospecha de toxoplasmosis congénita. 1970 se publicó artículo con nombre de Citomegalovirus.

4 EPIDEMIOLOGÍA Entre 50% y 80% de adultos en Estados Unidos son infectados a los 40 años. Es el virus más comúnmente transmitido de madre a hijo. Aprox. 1 de cada 150 niños nace con infección congénita. Aprox. 1 de cada 750 niños nace con o desarrolla discapacidades permanentes relacionadas con CMV. Aprox niños sufren de discapacidaes permanentes.

5 SOBRE EL VIRUS Prevalece en países en desarrollo y áreas de condiciones socioeconómicas bajas. Miembro de la familia herpes virus. Se encuentra en líquidos corporales (orina, saliva, leche materna, sangre, lágrimas, semen y líquido vaginal). Una vez infectada una persona, el virus permanece latente. Infección silenciosa y oportunista.

6 RUTA DE INFECCIÓN 0-2 años  cérvix uterino de la madre, leche materna, saliva y orina. Sexualmente activos (heterosexuales y homosexuales). CMV seropositivo o infección latente  duración actividad sexual, número de parejas y antecedentes de sífilis.

7 RUTA DE ENTRADA

8

9

10

11 RESPUESTA INMUNE INNATA

12

13 A | Immunoevasins of murine cytomegalovirus (mCMV)
A | Immunoevasins of murine cytomegalovirus (mCMV). a | m04 binds to MHC class I molecules in the endoplasmic reticulum (ER) and escorts them to the cell surface. By passing through the Golgi apparatus, it acquires two endoglycosidase-H-resistant oligosaccharide chains. MHC class I molecules and m04 can be co-precipitated from the cell surface. The complex does not seem to be recognized by CD8+ T cells. It is unclear whether the complexed MHC molecules do not present peptide or whether the bound m04 prevents recognition. m04-mediated surface display of MHC class I molecules might silence natural killer (NK) cells77, 78. b | m06 binds through a lumenal domain to peptide-loaded MHC class I molecules in the ER and reroutes the resulting complex to a late endosomal/lysosomal compartment for degradation. A di-leucine motif in the cytoplasmic tail of m06 is required for this function128. c | m152 triggers the retention and accumulation of peptide-loaded MHC class I molecules in the ER Golgi intermediate compartment (ERGIC). It does not form stable complexes with class I molecules. It seems to associate transiently and induce a modification of MHC class I complexes that might prevent their interaction with cargo receptors61, 62, 63, 64. B | Immunoevasins of human cytomegalovirus (hCMV). a | US6 blocks peptide translocation through the transporter for antigen processing (TAP) by interaction with the lumenal surfaces of both subunits of the TAP1–TAP2 heterodimer in the transient peptide-loading complex — which consists of TAP, the MHC class I complex and ER-resident chaperones. It does not interfere with peptide binding to the cytosolic surface of TAP. It is proposed that a conformational change inhibits ATP-dependent peptide translocation by the prevention of ATP binding to the cytosolic nucleotide-binding domain of TAP129, 130, 131. b | US3 is an immediate-early (IE) protein that causes retention of peptide-loaded MHC class I molecules in the ER. Its lumenal domain is sufficient for retention, whereas binding to class I molecules requires, in addition, the transmembrane segment. US3-bound complexes are degraded in the early (E) phase by US2- and/or US11-mediated mechanisms66, 67. c | US2 and US11 both induce rapid proteasomal degradation of MHC class I -chains by mediating retrograde translocation from the ER to the cytosol. As has been shown for US2, retrograde translocation involves the 'translocon', a pore complex that is formed by the Sec61 –– heterotrimer and translocating chain-associating membrane protein (TRAM)69. US2 and US11 can bind to unfolded -chains, as well as to the folded MHC class I molecules. The crystal structure of US2 in complex with HLA-A2 reveals binding of US2 to the junction between the class I 3 domain and the peptide-binding region132. Unlike US11, which remains in the ER membrane, US2 seems to be co-dislocated and to escort the MHC class I -chain to the cytosol71. L, late phase.

14 a | Conditional peptide presentation induced by interferon- (IFN-)
a | Conditional peptide presentation induced by interferon- (IFN-). In the early (E) phase (left-hand side), murine cytomegalovirus (mCMV) IE1 protein is processed, but presentation of the IE1 peptide is prevented by m152-triggered retention of peptide-loaded MHC class I H-2Ld molecules in the endoplasmic reticulum (ER) Golgi intermediate compartment (ERGIC)61, 63. After pre-treatment of the cells with IFN- (right-hand side), enhanced processing of the IE1 peptide by the immunoproteasome123, most probably combined with upregulation of expression of MHC class I molecules and of the transporter for antigen processing (TAP), leads to the escape of sufficient IE1–H-2Ld complexes for recognition by IE1-peptide-specific cytotoxic T lymphocytes (CTLs) at the cell surface100. b | Constitutive peptide presentation. There are viral peptides for which presentation in the presence of immunoevasins does not require IFN-34,42, 72. A peptide derived from mCMV E-phase protein m164, a putative glycoprotein with two predicted membrane-spanning -helices, is processed during the E phase in fibroblasts in approximately tenfold excess over the IE1 peptide. Although the IE1 peptide is not presented, the same cells are lysed by CTLs specific for the m164-derived peptide103. TCR, T-cell receptor.

15

16 INFECCIÓN CMV Aislamiento del virus o detección de proteínas virales ó ácido nucleico en cualquier líquido corporal o tejido.

17 INFECCIÓN PRIMARIA CMV
Detección de infección por CMV en un individuo previamente sano (seronegativo para CMV). Aparición de anticuerpos específicos de novo en un paciente sano (seronegativo para CMV).

18 INFECCIÓN RECURRENTE CMV
Nueva detección de infección por CMV en un paciente que tenía una infección documentada previa y que no se había detectado al virus en las cuatro semanas previas.

19 REINFECCIÓN Detección de una cepa de CMV que es distinto de una cepa que era la causa de la infección original. Se pueden identificar regiones específicas en el genoma o usando técnicas moleculares que examinan los genes polimórficos.

20 REACTIVACIÓN Si la misma cepa es identificada, ya sea por región específica del genoma o por técnica molecular en genes polimórficos.

21 TRANSMISIÓN Transmisión de persona a persona, por contacto directo con líquidos corporales. En Estados Unidos, alrededor de 1 – 4% de madres no infectadas tiene infección primaria durante el embarazo. 33% de las mujeres que se infectan con CMV por primera vez durante el embarazo lo transmiten a sus productos.

22

23 Congenital Cytomegalovirus Infection
A baby girl was delivered prematurely, at 30 weeks' gestation, by emergency cesarean section owing to deceleration and no acceleration on fetal heart-rate monitoring. In addition, she had severe intrauterine growth restriction, oligohydramnios, and increased peak systolic velocity of the middle cerebral artery on Doppler ultrasonography. The 39-year-old mother (gravida 7, para 5) had been well during the pregnancy. On examination, the neonate was found to have respiratory distress, an extensive rash (Panel A), and hepatomegaly. The rash consisted of purple-to-magenta, nonblanching macules that were 0.5 to 1.0 cm in diameter, as well as papules and petechiae covering her entire body. Laboratory investigation revealed anemia (hemoglobin level, 25 g per liter [normal range, 121 to 191]) and thrombocytopenia (platelet count, 13×109 per liter [normal range, 195 to 434]). Results of cytomegalovirus (CMV) IgM and IgG tests and both serum and plasma DNA polymerase-chain-reaction assays were positive. Tests for parvovirus B19 and rubella IgM antibodies were negative. Despite aggressive care, the child did not survive. Postmortem examination confirmed disseminated CMV infection. Extramedullary hematopoiesis was present throughout the body, including the skin (Panel B). Dermal hematopoiesis can occur in utero as a result of severe anemia, congenital rubella, parvovirus infection, or CMV infection. Abdel-Latif ME, Sugo E. N Engl J Med 2010;362:

24

25

26

27

28

29

30

31