Course Of Primary Infection Research Articles

Isotype-specific serum IgG responses of llamas ( Lama glama) to experimental liver fluke infection

The humoral immune system of South American camelids is unusual in that a large component of the IgG comprises heavy chains only. The objective of this study was to assess the contribution of these and conventional four chain IgG antibodies to the immune response of llamas in the course of primary infections with the liver fluke Fasciola hepatica. Isotypes of IgG were isolated by affinity chromatography and the production of various isotypes determined by ELISA. Both conventional and heavy-chain only isotypes of F. hepatica-specific IgG were detected in the course of the infection. The conventional four-chain antibody, IgG1, predominated but a marked increase was also detected in the heavy-chain only isotype IgG3. IgG2, another heavy-chain only isotype, was a minor component of the fluke specific response.

Cytokine and chemokine gene expression after primary and secondary respiratory syncytial virus infection in cotton rats.

The induction of pro- and anti-inflammatory cytokines and chemokines was studied in the lungs of cotton rats after primary or secondary infection with respiratory syncytial virus (RSV). Increases in messenger RNA (mRNA) levels of all genes analyzed were observed during the course of primary infection. In general, mRNA expression peaked between postinfection days 1 and 4 and returned to near-normal levels by day 10. During secondary infection, the expression of some genes (i.e., interferon [IFN]-gamma and interleukin [IL]-10) began earlier, some (i.e., IL-1beta and macrophage inflammatory protein-1beta) began later, and some (i.e., IL-1beta, IL-10, growth-regulated protein, and tumor necrosis factor-alpha) showed prolonged expression, whereas 2 genes (i.e., IFN-alpha and IL-6) were not expressed. This study presents evidence of different kinetics of expression of inflammatory mediators during primary and secondary infection that likely coincide with innate and adaptive immune response and complement previous observations that emphasize the role of inflammation in the pathogenesis of RSV disease.

Variable fate of virus-specific CD4+ T cells during primary HIV-1 infection

Impairment of CD4(+) T lymphocyte responses to human immunodeficiency virus (HIV)-derived antigens is the classic immunological defect observed during the chronic phase of HIV-1 infection. Early intervention with potent antiretroviral therapy (ART) can preserve HIV-specific CD4(+) T lymphocyte reactivity, providing indirect evidence that such responses are mounted during primary infection and subsequently lost in the majority of infected individuals. Here, we demonstrate early and dramatic expansions of functional HIV-specific CD4(+) T lymphocyte frequencies directly ex vivo. These responses are initially of broad specificity, and can disappear rapidly during the natural course of primary infection. This process of loss is variable, such that the rapidity and extent of functional compromise differs between individuals. Institution of ART during these early phases of HIV-1 infection preserves patterns of functional reactivity within the HIV-specific CD4(+) T lymphocyte population. However, there was no evidence for the restoration of deleted responses. These findings indicate that, in some individuals at least, ART must be administered within a narrow window of opportunity during primary HIV-1 infection to effect substantial immune preservation.

Variable fate of virus-specific CD4(+) T cells during primary HIV-1 infection.

Impairment of CD4(+) T lymphocyte responses to human immunodeficiency virus (HIV)-derived antigens is the classic immunological defect observed during the chronic phase of HIV-1 infection. Early intervention with potent antiretroviral therapy (ART) can preserve HIV-specific CD4(+) T lymphocyte reactivity, providing indirect evidence that such responses are mounted during primary infection and subsequently lost in the majority of infected individuals. Here, we demonstrate early and dramatic expansions of functional HIV-specific CD4(+) T lymphocyte frequencies directly ex vivo. These responses are initially of broad specificity, and can disappear rapidly during the natural course of primary infection. This process of loss is variable, such that the rapidity and extent of functional compromise differs between individuals. Institution of ART during these early phases of HIV-1 infection preserves patterns of functional reactivity within the HIV-specific CD4(+) T lymphocyte population. However, there was no evidence for the restoration of deleted responses. These findings indicate that, in some individuals at least, ART must be administered within a narrow window of opportunity during primary HIV-1 infection to effect substantial immune preservation.

Low cell dosage of lymphoblastoid human cell lines EBV(+) is associated to chronic hepatitis in a minority of inoculated Nu/Nu mice.

It has been suggested that an atypical course of primary infection by EBV and the reactivation of EBV infection in transplanted patients may induce hepatitis. We explored the possibility to dissect the infectious activity from the ability to promote B lymphocyte proliferation in vivo by injecting in nu/nu mice a low number (2 x 10(6)-0.05 x 10(6)) of cells from CE a normal human bone marrow-derived B cell line. This line carries an endogenous EBV in episomal and linear forms. Twenty nu/nu mice were inoculated subcutaneously with the B cell line CE and a matched group with the cell line RAG obtained by EBV in vitro infection of normal human peripheral blood. The mice injected with the CE line did not develop a lymphoproliferative disease, but 5 of them displayed typical histopathological lesions of chronic hepatitis without involvement of other organs. Similar results were obtained in 2 out of 20 animals in the RAG group. A close association between liver lesions and a previous EBV infection, by putative circulating B lymphoblastoid cells releasing their EBV, was established by PCR and by in situ hybridization with BamHI "W" DNA probe. This latter probe detected the presence of about 15% of positive cells only in affected livers. In addition, the rare detection in some hepatocytes of "A" type Cowdry bodies would suggest the occurrence of continuous EBV replication although at a very low level. These data show that we succeeded in dissecting the infectious from the proliferative activity of the endogenous EBV carrier CE cell line. This provides in addition a promising model for chronic EBV-associated hepatitis.

Interleukin-6 is produced during both murine and avian Eimeria infections

The production of interleukin-6 (IL-6) during Eimeria infection was investigated in an attempt to gain a better understanding of the role of this multi-functional cytokine in resistance to this parasite. IL-6 production was measured in both chickens, in which the disease is of economic importance, and the better-characterised murine model system. Systemic and local IL-6 production in mice during E. vermiformis infection was investigated, in the relatively resistant BALB/c strain, and the relatively susceptible C57 BL/6 strain, using a murine IL-6 ELISA and the 7TD1 assay. Enhanced systemic production of IL-6 in serum was seen in infected BALB/c mice when compared to C57 BL/6 mice. This difference was also reflected in the draining lymph node of the site of infection, assessed by testing supernatants from stimulated mesenteric lymph node cells taken from infected mice at different times post-infection. Production of chicken IL-6-like factor activity was investigated using a murine IL-6 7TD1 bioassay. The presence of substantial quantities of IL-6-like factor activity was detected in serum taken from some chickens infected with E. tenella during the course of primary infection and, in a separate experiment, during the first few hours post-infection, a time when the pro-inflammatory capacity of IL-6 would influence the developing immune response. These results suggest that IL-6 is also important in the induction of immune effector responses to Eimeria infections in the chicken.

Participation of the Dengue virus in the fibrinolytic process.

To date, the phatophysiology of hemorrhagic dengue is still unknown and hypotheses which aim to explain the unfortunate cases of the disease (hemorrhagic fever/shock syndrome) are based on epidemiological data and favor the notion of the participation of heterotypic non-neutralizing antibodies during the course of secondary infection (immunologic status of the host). However, cases of hemorrhagic dengue have been reported during the course of primary infections. We propose that the dengue virus, specifically the envelope glycoprotein can participate directly in the installation of the hemorrhagic phenomenon by means of the binding and activation of plasminogen (PLG) as condition previous to the development of the fibrinolytic process. Based on this hypothesis, we evaluated the biological activity of some viral isolates proceeding from hemorrhagic and from dengue fever cases in an in vitro model of fibrinolysis. Dengue isolates were capable of activating PLG. The plasmin generated specifically degraded the fibrin/fibrinogen molecule. This catalytic process can be prevented by the presence of the specific plasmin inhibitor, alpha-2-antiplasmin, for virus isolates from dengue fever, but not for isolates associated with dengue hemorrhagic disease, favoring the exacerbation of the fibrinolytic activity. This new approach allows us to suggest the importance of viral factors in the dengue hemorrhagic fever.

Prognostic value of serum HIV-RNA levels at virologic steady state after seroconversion: relation to CD4 cell count and clinical course of primary infection.

The objectives of this study were to evaluate the prognostic value of a single serum HIV-RNA measurement 6-24 months after HIV seroconversion, and to investigate whether any differences in outcome related to the clinical course of primary infection could be explained by presumed steady-state HIV-RNA levels at 6-24 months after seroconversion. Disease progression was analyzed by life tables and Cox proportional hazard models. A total of 93 HIV seroconverters followed for a median of 76 months (range, 19-143 months) were included in the study. The main outcome measures were development of AIDS stratified by age, the year of seroconversion, serum HIV-RNA levels, CD4 cell counts, and duration of primary illness. The proportion of patients who developed AIDS was 36% (95% confidence interval, 22%-50%) at 8 years and 50% (26%-75%) at 10 years. In the unadjusted analyses, clinical progression was significantly associated with serum HIV-RNA levels, CD4 cell counts, and duration of primary illness. The adjusted analyses indicated that HIV-RNA was the strongest predictor. Patients with long-lasting symptoms associated with primary infection had significantly higher serum HIV-RNA levels than those with less severe presentations (median counts, 11,660 vs. 2880 copies/ml, p = 0.001). It is concluded that the serum HIV-RNA level in early HIV infection is a strong independent predictor of clinical progression. Patients with long-lasting primary illnesses reach a higher viral load in steady state after seroconversion, which is probably the main reason for the poorer prognosis observed in this group of patients.

IL-15 is a novel growth factor for murine gamma delta T cells induced by Salmonella infection.

Abstract We have previously shown evidence for the early recruitment of gamma delta T cells during the disease course of primary infections with Listeria monocytogenes or Salmonella choleraesuis in mice. Since gamma delta T cells at this stage of the disease do not produce IL-2, the growth factor for the gamma delta T cells remains unknown. IL-15 is a novel cytokine that uses beta- and gamma-chain of IL-2R for signal transduction, and is produced by activated monocytes/macrophages. In this study, we investigated the proliferative activity of IL-15 for gamma delta T cells appearing after primary infection with S. choleraesuis 31N-1. The gamma delta T cells, which expressed beta- and gamma-chains of IL-2R, proliferated in the presence of rIL-15 and produced appreciable levels of gamma-IFN and IL-4. Addition of anti-IL-2R beta mAb significantly inhibited the IL-15-induced proliferation of the gamma delta T cells. Furthermore, the gamma delta T cells produced gamma-IFN in response to monocyte/macrophage cell line, J774A.1 infected with S. choleraesuis, which expressed an abundant level of IL-15 mRNA. This cytokine production was inhibited significantly by anti-IL-15 Ab. Taken together, these results suggest that IL-15 derived from infected macrophages may contribute to the early activation of gamma delta T cells during salmonellosis.

Avian coccidiosis: changes in intestinal lymphocyte populations associated with the development of immunity to Eimeria maxima.

The effect of infection and subsequent challenge with Eimeria maxima on the populations of lymphocytes in the small intestine of Light Sussex chickens was assessed by immunohistochemistry. T cells were characterized for CD3, CD4, CD8, TCR1 (gamma delta heterodimer) or TCR2 (alpha beta 1 heterodimer) markers, and B cells for the expression of IgM, IgA and IgG. After a primary inoculum there were, in both the epithelium and the lamina propria, two distinct increases in the numbers of T lymphocytes. The first peaked on days 3-5 and the second, greater influx, on day 11 after infection. CD4+ and CD8+ cells were represented in both peaks but, whereas CD4+ cells were found almost exclusively in the lamina propria, CD8+ cells were present in both sites. The area staining positive for CD8+ cells was somewhat greater than the value obtained for CD4+ cells. In the epithelium there was an early, small increase in TCR1(+)-staining, followed by a larger rise to the second peak, at which time there was also an increase in the lamina propria. Staining for TCR2+ cells followed the same pattern with a reversed distribution between epithelium and lamina propria. Changes after challenge were minimal and confined to the epithelium. The most notable changes in the expression of immunoglobulins were, in the lamina propria, a biphasic increase in the amount of IgM(+)-staining in the course of primary infection (corresponding approximately to that of the T cells), and in IgA+ cells shortly after challenge.

Course of primary candidiasis in T cell-depleted mice infected with attenuated variant cells.

Anti-CD4, anti-CD8, or anti-interferon-gamma (IFN-gamma) antibodies or combinations of them were administered in the early stages of chronic infection of mice with a Candida albicans live vaccine strain, and the animals were monitored for course of primary infection, development of delayed-type hypersensitivity, resistance to reinfection, production of interleukin 2 (IL-2) and IFN-gamma in vitro by splenic lymphocytes, and levels of IL-2 and IFN-gamma transcripts in these cells. CD4+ cell and IFN-gamma depletion resulted in the development of fatal candidiasis by the attenuated yeast vaccine. In contrast, either treatment alone modified the course but not the outcome of primary infection, though each prevented the development of resistance to reinfection. Our data thus indicate that both IFN-gamma and CD4+ cells participate in resistance to primary infection with attenuated yeast cells and are critical in the induction of persistent systemic anticandidal immunity.

Analyzing the distribution of cells expressing mRNA for T cell receptor γ and δ chains in a virus-induced inflammatory process

Acute inflammatory processes are extremely complex, containing sets of activated cells that may be difficult to categorize. The interface between two methodologies for characterizing the involvement of γδ T cells, in situ hybridization to detect T cell receptor (TCR) mRNA and flow cytometric analysis of surface TCR expression, is utilized here to study the pneumonia caused by intranasal (i.n.) infection of mice with influenza A viruses. Substantial numbers of cells expressing mRNA for the γ and δ TCR chains are present in bronchoalveolar lavage (BAL) populations obtained either late in the course of primary infection with an H3N2 virus or within a few days of secondary challenge with an H1N1 virus. The majority of the γδ TCR mRNA + cells detected in FACS-separated BAL populations partition to the Thy1 + γδ TCR + subset, while relatively few (<10%) Cδ mRNA transcripts are found in cells that phagocytose latex particles. However, an additional set of γδ TCR mRNA + cells is also located in a high side scatter (H-SSC) population, which stains nonspecifically with monoclonal antibodies (mAbs) and is normally gated out in the process of flow cytometric analysis. This H-SSC population tends to be enriched for cells expressing Cγ 1 2 rather than Cγ4 mRNA. While some γδ TCR lymphocytes can be demonstrated by in vitro stimulation of the CD3ϵ + subset within this H-SSC population, the majority of the γδ T cell precursors that can be expanded in culture demonstrate a low side scatter (L-SSC) profile more characteristic of normal T lymphocytes. The possibility that subsets of activated, granular (H-SSC) αβ TCR + and Cγ 1 2 mRNA + γδ T cells are being missed when conventional FACS analysis is used to study this viral pneumonia is discussed.

Free radical generation and the course of primary infection with Nippostvongylus brasiliensis in congenitally athymic (nude) rats

The course of primary infections with Nippostrongylus brasiliensis was followed in nude (CBH/R nu/nu) and heterozygote (CBH/R nu/+) rats. In both nude and heterozygote rats peak egg production by N. brasiliensis occurred on days 7 and 8 post-infection. However, whereas in heterozygote rats egg production declined rapidly thereafter and ceased completely by day 14 post-infection, in nude rats high numbers of N. brasiliensis eggs were still seen on day 27 post-infection, when the experiment was terminated. In comparison with the nude rats, heterozygote rats had a 5-fold greater loss of weight by day 9 post-infection and a 4-fold higher incidence of diarrhoea. Furthermore, infected heterozygote rats became anaemic whereas uninfected rats and infected nude rats showed no evidence of anaemia. Free radical generation was measured in infected (9 days) and uninfected rats. Leucocytes from infected heterozygote rats were able to generate copious quantities of free radicals in response to N. brasiliensis whereas leucocytes from infected nude rats produced only slightly more free radicals than uninfected rats. Thus, worm rejection, weight loss, diarrhoea, anaemia and free radical generation in response to N. brasiliensis infection are all T-cell dependent events.

Immunological relationships during primary infection withHeligmosomoides polygyrus(Nematospiroides dubius): H-2 linked genes determine worm survival

The course of primary infection was studied in BALB and B10 H-2 congenic mouse strains. The duration of infection, as assessed with regular faecal egg counts and worm burdens, was shorter in mice carrying the H-2s, H-2d or H-2q haplotypes when compared to mice with H-2b. Strains with H-2k were intermediate. An experiment was carried out to test the hypothesis proposed by Wassom, Krco & David (1987) predicting that the progeny of I-E+ve mouse strains crossed with I-E-ve strains, would show susceptibility rather than resistance to infection. This hypothesis was not substantiated by our data and we conclude that it does not apply to primary infections with Heligmosomoides polygyrus. It is proposed that the gene products of at least two loci within the H-2 (associated with the H-2b and H-2k haplotypes) are crucial in determining the response phenotype of mice to primary infection with H. polygyrus. One allele, (associated with the H-2b haplotype) may be preferentially affected by parasite-mediated immunosuppression.

Echinostoma caproni in rats: worm population dynamics and host blood eosinophilia during primary infections with 6, 25 and 50 metacercariae and resistance to secondary and superimposed infections

Hooded-Lister rats were inoculated with 6, 25, 50 or 100 metacercariae of the intestinal trematode Echinostoma caproni. Worm establishment and the pattern of egg excretion were followed during the course of primary infections with 6, 25 and 50 metacercariae. Peripheral blood eosinophilia was followed at all infection levels. After 1 month, worm recovery and faecal egg output showed a gradual decline with increasing duration of infection. High worm burdens were expelled later than smaller worm burdens, and egg output persisted longer in animals exhibiting a high initial egg output. The level of blood eosinophilia increased with increasing degree of infection and with the level of egg output. A marked concomitant resistance to superimposed infection was observed on the challenge of rats harbouring 21- and 49-day-old infections with 50 metacercariae. In addition, rats were partially resistant to secondary infection at challenge day 14 following anthelmintic removal of primary 7-day-old infections with 50 metacercariae and were completely resistant at challenge day 7 following elimination of a primary 14-day-old primary infection.

Eimeria vermiformis: Differences in the course of primary infection can be correlated with lymphocyte responsiveness in the BALB/c and C57BL/6 mouse, Mus musculus

BALB/c and C57BL/6 mice are high- and low-responders, respectively, to infection with Eimeria vermiformis, this genetically determined difference being immunologically mediated. In order to identify the level at which response phenotype is determined, the proliferation of mesenteric lymph node cells and their ability to transfer immunity adoptively were investigated in each strain; the development of circulating serum antibodies to E. vermiformis was also determined. In all respects BALB/c mice responded earlier than the C57BL/ 6 but peak values were similar in both strains. The relationship between the temporal differences noted and the characteristic, differing course of the primary infection in the two strains is discussed.

Pattern of anti-cytomegalovirus IgM antibodies determined by immunoblotting

In order to improve the knowledge of the humoral immune response to CMV infection, we developed an immunoblotting technique which allowed a better analysis of the changes in the pattern of anti CMV-polypeptides IgM. We examined 234 sera belonging to 27 renal allograft recipients developing a primary or recurrent CMV infection and 12 non infected recipients. Thus we found that 11 main anti CMV-polypeptides IgM antibodies were present in over 25% of the infected patients. They reacted with proteins whose molecular weights ranged from 32K to 205K. We showed that anti-p 45-47 IgM antibodies were present in 100% of CMV infected recipients and never in the non-infected population. They appeared very early in the course of the infection (5.43 weeks post-graft for primary infection and 5.00 weeks for recurrent ones) and, therefore, constitute a good marker of active infection. Two other CMV-specific IgM antibodies (anti-p 60-64 and anti-p 100) were found exclusively in the course of primary infections. Anti-p 60-64 IgM was observed at a high frequency (57.1%) and with a mean delay of 6.57 weeks post-graft. Therefore, the anti-p 60-64 IgM detection could be helpful for the diagnosis of primary infection. In almost 100% of both primary and recurrent infections, we observed anti-p 140 and anti-p 38 IgM antibodies. Only about 50% of non-infected patients had low levels of anti-p 140 and anti-p 38 IgM. The follow-up of recurrent infections showed that the anti CMV-polypeptides IgM antibodies appeared earlier than in primary infection. When we compared anti-p 45-47 IgM detection by immunoblotting and anti-CMV IgM detected by ELISA we observed that immunoblotting permitted the diagnosis 2.5 weeks earlier for primary infection, and 1 week earlier for recurrent infection, than ELISA. In addition, the detection of anti-p 45-47 IgM antibodies also occurred earlier than virus excretion.

Clinical course of primary HIV infection: consequences for subsequent course of infection.

To investigate the impact of the clinical course of the primary HIV infection on the subsequent course of the infection. Prospective documenting of seroconversion, follow up at six month intervals, and analysis of disease progression by life tables. 86 Men in whom seroconversion occurred within 12 months. Progression of HIV infection, defined as CD4 lymphocyte count less than 0.5 X 10(9)/l, recurrence of HIV antigenaemia, or progression to Centers for Disease Control group IV. Median follow up was 670 (range 45-1506) days. An acute illness like glandular fever occurred in 46 (53%) subjects. Three year progression rates to Centers for Disease Control group IV was 78% at three years for those who had longlasting illnesses (duration greater than or equal to 14 days) during seroconversion as compared with 10% for those who were free of symptoms or had mild illness. All six patients who developed AIDS had had longlasting primary illnesses. Three year progression rates to a CD4 lymphocyte count less than 0.5 X 10(9)/l and to recurrence of HIV antigenaemia were significantly higher for those who had longlasting primary illnesses than those who had no symptoms or mild illness (75% v 42% and 55% v 14%, respectively). The course of primary infection may determine the subsequent course of the infection.

Ancylostoma ceylanicum in the hamster: observations on the host-parasite relationship during primary infection.

The course of primary infection with a hamster-adapted strain of Ancylostoma ceylanicum was studied in inbred DSN and randomly bred WO/GD and WO/CR hamsters. Infective larvae were administered orally and began to develop in the small intestine without embarking on a tissue migration. Only the occasional larva was detected in other organ sites. It was concluded that the developing larvae moulted on days 3-4 and again to the pre-adult stage about 9-11 days post-infection. Worm burdens in infected hamsters were stable for at least 11 weeks after infection. There was no sudden expulsive phase and some adult worms survived for over 200 days. Overall the sex ratio of worms in groups of hamsters killed concurrently was about 50% although occasionally the ratio was biased in favour of one sex in individual animals. The blood packed cell volume (PCV) was significantly depressed 2 weeks following infection and continued to decline until a point of stability was achieved 4-5 weeks post-infection. The PCV subsequently remained depressed throughout the period of observation. Infected hamsters lost weight if kept in groups, but not when housed in separate cages. Groups of animals which lost weight did not recover to normal values within 11 weeks of infection. It is suggested that this model of hookworm infection has scope for exploring aspects of the host-parasite relationship which the canine models cannot fulfill adequately.

The course of primary infection with Necator Americanus in syngeneic mice

Wells C. and Behnke J. M. 1988. The course of primary infection with Necator americanus in syngeneic mice. International Journal for Parasitology 18: 47–51. A panel of syngeneic mouse strains was compared for susceptibility to infection with a hamster adapted strain of N. americanus. Lung worm burdens were compared 4–5 days after percutaneous exposure to 190–375 larvae. SJL and DBA/I were most susceptible. Balb/c, DBA/2 and CBA strains showed intermediate worm burdens and SWR, C 57BL 10, NIH and C3H/HR mice were the most resistant. NIH and Balb/c mice consistently showed significant differences in lung worm establishment and were selected for closer examination. The recovery of larvae from the skin on day 2 and the subsequent rate of loss from this site were similar in both strains. However, Balb/c mice developed significantly higher lung worm burden than NIH and the rate of loss from the lung was more rapid. L 4 larvae were first recovered from the small intestines of Balb/c mice on day 7, numbers reaching a peak on day 9 when the mean intestinal recovery corresponded to 10% of the peak lung burden. Intestinal stages were not found in NIH mice and no larvae were found in other tissue sites of either strain. The relevance of N. americanus in mice as a model for the study of host-parasite relationships of the invasive and migratory stages of hookworms is discussed.