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Cryptosporidium Parvum Infection in Gene-Targeted B Cell–Deficient Mice

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Cryptosporidium Parvum Infection in Gene-Targeted B Cell–Deficient Mice RESEARCH NOTES 391 switching in avian malaria parasites. Proceedings of the Royal So- VALKIUNAS, G. 1997. Bird Haemosporida. Acta Zoologica Lituanica 3± ciety of London B Biological Sciences 269: 885±892. 5: 1±607. SAMBROOK, J., E. F. FRITSCH, AND T. M ANIATIS. 1989. Molecular cloning, WALDENSTROÈ M, J., S. BENSCH,S.KIBOI,D.HASSELQUIST, AND U. OT- a laboratory manual. 2. Cold Spring Harbor Laboratory Press, Cold TOSSON. 2002. Cross-species infection of blood parasites between Spring Harbor, New York. resident and migratory songbirds in Africa. Molecular Ecology 11: SAS. 1990. SAS Institute Inc., Cary, North Carolina. 1545±1554. SOL, D., R. JOVANI, AND J. TORRES. 2000. Geographical variation in WEATHERHEAD, P. J. 1990. Secondary sexual traits, parasites, and po- blood parasites in feral pigeons: The role of vectors. Ecography lygyny in red-winged blackbirds, Agelaius phoeniceus. Behavioral 23: 307±314. Ecology 1: 125±130. J. Parasitol., 89(2), 2003, pp. 391±393 q American Society of Parasitologists 2003 Cryptosporidium parvum Infection in Gene-Targeted B Cell±De®cient Mice Wangxue Chen, James A. Harp*, and Allen G. Harmsen², Institute for Biological Sciences, National Research Council, 100 Sussex Drive, Ottawa, Canada K1A 0R6; *Periparturient Diseases of Cattle Research Unit, National Animal Disease Center, Agricultural Research Service, United States Department of Agriculture, Ames, Iowa 50010-0070; ²Department of Veterinary Molecular Biology, Montana State University, Bozeman, Montana 59717. e-mail: [email protected] ABSTRACT: The importance of B cells in host resistance to, and recov- is not suf®cient to resolve the infection (Soave and Johnson, 1988; Zu ery from, Cryptosporidium parvum infection was examined in gene- et al., 1992; Cozon et al., 1994). Direct evidence that B cells and an- targeted B cell±de®cient (mMT2/2) mice. Neonatal mMT2/2 mice in- tibody are not required for anti±C. parvum immunity was obtained in fected with C. parvum at 5 days of age completely cleared the infection the study by Taghi-Kilani et al. (1990), who showed that neonatal mice by day 20 PI. The kinetics of infection and clearance were similar to depleted of B cells by anti-m antibody treatment were able to control those seen with age-matched C57BL/6 control mice. Furthermore, B C. parvum infection as ef®ciently as control mice. Taken together, these cells were not required to clear existing C. parvum infection in adult ®ndings favor the notion that humoral immunity is not a requirement mice. Reconstitution of persistently infected Rag-12/2 adult mice with for clearing infection, and by itself is not suf®cient to control enteric spleen cells from mMT2/2 donor mice resulted in signi®cant reduction infection with C. parvum. of infection, as in the results seen with spleen cells from C57BL6 do- It is worth noting that the mice that were rendered B cell de®cient nors. These ®ndings indicate clearly that B cells are not essential for by anti-m antibody treatment (Taghi-Kilani et al., 1990) contained small host resistance to, and recovery from, C. parvum infection in mice. numbers (,5%) of sIg-expressing B cells in the spleen and lymph nodes and developed low amounts of serum and gut Ig of all isotypes. In Cryptosporidium parvum is an important cause of intestinal infections addition, the treatment with anti-m antibodies might have affected cells in immunocompromised humans, especially in acquired immunode®- other than B cells, making it dif®cult to assess these effects in an un- ciency syndrome (AIDS) patients, whereas the infection is usually self- equivocal manner (Langhorne et al., 1998). limiting and probably often undiagnosed in immunocompetent hosts Gene-targeted disruption of the IgH locus produces mice completely (Laughon et al., 1991; Zu et al., 1992). The mechanism of host resis- devoid of both antibodies and B cells (Kitamura et al., 1991). In the tance to, and recovery from, C. parvum infection remains poorly de- present study, we examined the requirement for B cells in resistance to ®ned. Recent clinical and experimental studies show that both CD41 initial C. parvum colonization by using these gene-targeted B cell±de- cells and interferon (IFN)-g are necessary for host resistance to C. par- ®cient mice (mMT2/2 mice). We also used these mice in splenocyte vum infection, whereas other components, including nitric oxide and transfer experiments to determine the importance of B cells in the res- interleukin (IL)-4, also may play a role (Ungar et al., 1991; Chen et al., olution of an established C. parvum infection. The results reported here 1993; Perryman et al., 1994; Aguirre et al., 1998; Leitch and He, 1999; showed that B cells are not essential for either resistance to C. parvum White et al., 2000). However, it is not known what other immune mech- colonization or resolution of an established C. parvum infection. anisms are involved in host defense against C. parvum infection. The C57BL/6J (B6) and C57BL/6J Igh-6tm1 Cgn (B cell de®cient, mMT2/ fact that C. parvum infection is self-limiting in nearly half the AIDS 2) mice were obtained from the Trudeau Institute Animal Breeding tm1 mom patients, with CD41 T cell counts in the circulation below 200 cells/ Facility (Saranac Lake, New York). C57BL/6J Rag-1 (Rag-12/2) mm3 (Flanigan et al., 1992), suggests that factors other than T cells also mice were purchased from Taconic Farms, Germantown, New York. play a role in controlling C. parvum infection. Indeed, the functions of Mice were housed in microisolator cages containing sterilized food and B cells and nonlymphoid cells in AIDS patients are also abnormal water and were shown to be free of an extensive series of common (Bowen et al., 1985), and this in turn could contribute to their increased murine pathogens including C. parvum. Age- and sex-matched mice susceptibility to C. parvum infection. were used in all the experiments. Puri®ed C. parvum oocysts, free of The importance of B cells in host defenses against C. parvum has bacterial contamination, were prepared from feces collected from calves not been well established, and the role of immunoglobulins in protective experimentally inoculated with C. parvum (Iowa isolate) by a method immunity against C. parvum remains controversial (McDonald and Ban- described previously (Harp et al., 1992). Mice were inoculated orally croft, 1998). Many groups have examined the kinetics of the production with a single dose of oocysts, as indicated in the text, in 0.2 ml of 0.15 of C. parvum±speci®c antibodies of different classes in the serum and M phosphate-buffered saline (pH 7.2) by using a 19g gavage needle. mucosal secretions and their association with oocyst shedding in in- To determine infection after C. parvum challenge, fecal pellets were fected humans, mice, cattle, and sheep (reviewed in McDonald and collected from individual mice and smeared onto glass slides. These Bancroft, 1998). Whereas some have found an association between de- smears were stained with carbol-fuchsin and examined for the presence clining oocyst shedding and rising titers of speci®c IgA and IgM, others of C. parvum oocysts as described previously (Waters and Harp, 1996). have failed to establish such an association. Several studies, however, Mice were killed by CO2 asphyxiation at the predetermined times. The suggest that humoral immunity has little protective effect on C. parvum ileum, cecum, and proximal colon were removed from each mouse and infection (Zu et al., 1992; McDonald and Bancroft, 1998; de Graaf et ®xed by immersion in 10% neutral buffered formalin. After ®xation, al., 1999; Weiner et al., 1999). The presence of high titers of C. parvum± the tissue was embedded in paraf®n. Sections of 4-mm thickness were speci®c antibodies in almost all the AIDS patients with persistent symp- cut, stained with hematoxylin±eosin (HE), and examined microscopi- tomatic cryptosporidiosis further implies that humoral immunity alone cally for C. parvum. An infectivity score of 0±3 was assigned to each 392 THE JOURNAL OF PARASITOLOGY, VOL. 89, NO. 2, APRIL 2003 TABLE I. Infectivity scores of Cryptosporidium parvum infection in the intestines of reconstituted Rag-12/2 mice.* Mean score² No. of Mouse group mice Ileum Cecum Colon Total Reconstituted with No cells (controls) 5 2.00 6 0.32 1.70 6 0.44 2.80 6 0.20 6.50 6 0.45 Spleen cells from mMT2/2 mice 5 0.80 6 0.49 0.0 6 0.0³ 0.80 6 0.38§ 1.60 6 0.81§ Spleen cells from B6 mice 4\ 0.38 6 0.24# 0.0 6 0.0³ 0.0 6 0.0§ 0.38 6 0.24§ * Mice were challenged with 107 oocysts per mouse, and reconstitution was done 19 days after challenge. All the animals were killed 17 days after reconstitution. ² Data are the mean 6 SEM infectivity scores based on histopathological examination as described in the text. ³ Signi®cantly different from the control value, P , 0.01. § Signi®cantly different from the control value, P , 0.001. \ One mouse died of an undetermined cause 29 days after oral C. parvum challenge. # Signi®cantly different from the control value, P , 0.05. section on the basis of the method described previously (Harp et al., vum infection in mice is B cell dependent. It should be noted that C. 1992; Chen et al., 1993), where 0 indicates no parasites observed; 11, parvum can colonize mouse strains with various immunode®ciencies small numbers of parasites distributed focally in the tissue (,10% of and can cause severe infection. Nu/nu mice, severe combined immu- the tissue colonized); 21, moderate numbers of parasites distributed node®ciency (SCID) mice, Rag-12/2 mice, TCRab2/2 mice, IFN-g2/ widely throughout the tissue (10±30% of the tissue colonized); and 31, 2 mice, CD40 and CD40L2/2 mice, mice treated with aminoguanidine large numbers of parasites widely distributed throughout the tissue (an inhibitor of inducible nitric oxide synthase), NOS22/2 mice, and (.30% of the tissue colonized).
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