Homologous Reinfection Research Articles

Waning immunity drives respiratory virus evolution and reinfection.

Reinfections with respiratory viruses such as influenza viruses and coronaviruses are thought to be driven by ongoing antigenic immune escape in the viral population. However, this does not explain why antigenic variation is frequently observed in these viruses relative to viruses such as measles that undergo systemic replication. Here, we suggest that the rapid rate of waning immunity in the respiratory tract is the key driver of antigenic evolution in respiratory viruses. Waning immunity results in hosts with immunity levels that protect against homologous reinfection but are insufficient to protect against infection with a heterologous, antigenically different strain. As such, when partially immune hosts are present at a high enough density, an immune escape variant can invade the viral population even though that variant cannot infect fully immune hosts. Invasion can occur even when the variant's immune escape mutation incurs a fitness cost, and we expect the expanding mutant population will evolve compensatory mutations that mitigate this cost. Thus the mutant lineage should replace the wild-type, and as immunity to it builds, the process will repeat. Our model provides a new explanation for the pattern of successive emergence and replacement of antigenic variants that has been observed in many respiratory viruses. We discuss our model relative to others for understanding the drivers of antigenic evolution in these and other respiratory viruses.

Lung infection with classical Klebsiella pneumoniae strains establishes robust macrophage-dependent protection against heterologous reinfection

At present, there is no approved vaccine for prevention of infection by the opportunistic bacterium Klebsiella pneumoniae (Kp); success in treating these infections is increasingly challenged by the spread of antibiotic resistance. Preclinical investigation of adaptive immunity elicited by lung infection with live classical Kp may reveal host mechanisms of protection against this pathogen. Here, we utilize multiple virulent classical Kp strains to demonstrate that following lung infection, surviving wild-type mice develop protective immunity against both homologous and heterologous (heterotypic) reinfection. For Kp strains with low capacity to disseminate from the lung, this immunity is B-cell-independent. We further demonstrate that this immune protection is also effective against subsequent challenge with hypervirulent Kp if the strains share the same capsule type. Systemic inoculation fails to elicit the same protective effect as lung inoculation, revealing a lung-specific immune effector function is responsible for this protection. We therefore utilized clodronate-loaded liposomes to substantially deplete both alveolar macrophages and lung interstitial macrophages, finding that simultaneous depletion of both subsets entirely ablates protection. These findings indicate that following initial lung infection with Kp, lung macrophages mediate protection against ensuing Kp challenge.

Symptomatic malaria enhances protection from reinfection with homologous Plasmodium falciparum parasites.

A signature remains elusive of naturally-acquired immunity against Plasmodium falciparum. We identified P. falciparum in a 14-month cohort of 239 people in Kenya, genotyped at immunogenic parasite targets expressed in the pre-erythrocytic (circumsporozoite protein, CSP) and blood (apical membrane antigen 1, AMA-1) stages, and classified into epitope type based on variants in the DV10, Th2R, and Th3R epitopes in CSP and the c1L region of AMA-1. Compared to asymptomatic index infections, symptomatic malaria was associated with reduced reinfection by parasites bearing homologous CSP-Th2R (adjusted hazard ratio [aHR]:0.63; 95% CI:0.45-0.89; p = 0.008) CSP-Th3R (aHR:0.71; 95% CI:0.52-0.97; p = 0.033), and AMA-1 c1L (aHR:0.63; 95% CI:0.43-0.94; p = 0.022) epitope types. The association of symptomatic malaria with reduced hazard of homologous reinfection was strongest for rare epitope types. Symptomatic malaria provides more durable protection against reinfection with parasites bearing homologous epitope types. The phenotype represents a legible molecular epidemiologic signature of naturally-acquired immunity by which to identify new antigen targets.

4'-Fluorouridine mitigates lethal infection with pandemic human and highly pathogenic avian influenza viruses.

Influenza outbreaks are associated with substantial morbidity, mortality and economic burden. Next generation antivirals are needed to treat seasonal infections and prepare against zoonotic spillover of avian influenza viruses with pandemic potential. Having previously identified oral efficacy of the nucleoside analog 4'-Fluorouridine (4'-FlU, EIDD-2749) against SARS-CoV-2 and respiratory syncytial virus (RSV), we explored activity of the compound against seasonal and highly pathogenic influenza (HPAI) viruses in cell culture, human airway epithelium (HAE) models, and/or two animal models, ferrets and mice, that assess IAV transmission and lethal viral pneumonia, respectively. 4'-FlU inhibited a panel of relevant influenza A and B viruses with nanomolar to sub-micromolar potency in HAE cells. In vitro polymerase assays revealed immediate chain termination of IAV polymerase after 4'-FlU incorporation, in contrast to delayed chain termination of SARS-CoV-2 and RSV polymerase. Once-daily oral treatment of ferrets with 2 mg/kg 4'-FlU initiated 12 hours after infection rapidly stopped virus shedding and prevented transmission to untreated sentinels. Treatment of mice infected with a lethal inoculum of pandemic A/CA/07/2009 (H1N1)pdm09 (pdmCa09) with 4'-FlU alleviated pneumonia. Three doses mediated complete survival when treatment was initiated up to 60 hours after infection, indicating a broad time window for effective intervention. Therapeutic oral 4'-FlU ensured survival of animals infected with HPAI A/VN/12/2003 (H5N1) and of immunocompromised mice infected with pdmCa09. Recoverees were protected against homologous reinfection. This study defines the mechanistic foundation for high sensitivity of influenza viruses to 4'-FlU and supports 4'-FlU as developmental candidate for the treatment of seasonal and pandemic influenza.

Homotypic protection against influenza in a pediatric cohort in Managua, Nicaragua

The period of protection from repeat infection following symptomatic influenza is not well established due to limited availability of longitudinal data. Using data from a pediatric cohort in Managua, Nicaragua, we examine the effects of natural influenza virus infection on subsequent infection with the same influenza virus subtype/lineage across multiple seasons, totaling 2,170 RT-PCR-confirmed symptomatic influenza infections. Logistic regression models assessed whether infection in the prior influenza season protected against homologous reinfection. We sequenced viruses from 2011–2019 identifying dominant clades and measuring antigenic distances between hemagglutinin clades. We observe homotypic protection from repeat infection in children infected with influenza A/H1N1pdm (OR 0.12, CI 0.02–0.88), A/H3N2 (OR 0.41, CI 0.24–0.73), and B/Victoria (OR 0.00, CI 0.00–0.14), but not with B/Yamagata viruses (OR 0.60, CI 0.09–2.10). Overall, protection wanes as time or antigenic distance increases. Individuals infected with one subtype or lineage of influenza virus have significantly lower odds of homologous reinfection for the following one to two years; after two years this protection wanes. This protection is demonstrated across multiple seasons, subtypes, and lineages among children.

Seasonality and immunity to laboratory-confirmed seasonal coronaviruses (HCoV-NL63, HCoV-OC43, and HCoV-229E): results from the Flu Watch cohort study.

Background: There is currently a pandemic caused by the novel coronavirus SARS-CoV-2. The intensity and duration of this first and second waves in the UK may be dependent on whether SARS-CoV-2 transmits more effectively in the winter than the summer and the UK Government response is partially built upon the assumption that those infected will develop immunity to reinfection in the short term. In this paper we examine evidence for seasonality and immunity to laboratory-confirmed seasonal coronavirus (HCoV) from a prospective cohort study in England. Methods: In this analysis of the Flu Watch cohort, we examine seasonal trends for PCR-confirmed coronavirus infections (HCoV-NL63, HCoV-OC43, and HCoV-229E) in all participants during winter seasons (2006-2007, 2007-2008, 2008-2009) and during the first wave of the 2009 H1N1 influenza pandemic (May-Sep 2009). We also included data from the pandemic and 'post-pandemic' winter seasons (2009-2010 and 2010-2011) to identify individuals with two confirmed HCoV infections and examine evidence for immunity against homologous reinfection. Results: We tested 1,104 swabs taken during respiratory illness and detected HCoV in 199 during the first four seasons. The rate of confirmed HCoV infection across all seasons was 390 (95% CI 338-448) per 100,000 person-weeks; highest in the Nov-Mar 2008/9 season at 674 (95%CI 537-835) per 100,000 person-weeks. The highest rate was in February at 759 (95% CI 580-975) per 100,000 person-weeks. Data collected during May-Sep 2009 showed there was small amounts of ongoing transmission, with four cases detected during this period. Eight participants had two confirmed infections, of which none had the same strain twice. Conclusion: Our results provide evidence that HCoV infection in England is most intense in winter, but that there is a small amount of ongoing transmission during summer periods. We found some evidence of immunity against homologous reinfection.

Seasonality and immunity to laboratory-confirmed seasonal coronaviruses (HCoV-NL63, HCoV-OC43, and HCoV-229E): results from the Flu Watch cohort study

Background: There is currently a pandemic caused by the novel coronavirus SARS-CoV-2. The intensity and duration of this first and second waves in the UK may be dependent on whether SARS-CoV-2 transmits more effectively in the winter than the summer and the UK Government response is partially built upon the assumption that those infected will develop immunity to reinfection in the short term. In this paper we examine evidence for seasonality and immunity to laboratory-confirmed seasonal coronavirus (HCoV) from a prospective cohort study in England. Methods: In this analysis of the Flu Watch cohort, we examine seasonal trends for PCR-confirmed coronavirus infections (HCoV-NL63, HCoV-OC43, and HCoV-229E) in all participants during winter seasons (2006-2007, 2007-2008, 2008-2009) and during the first wave of the 2009 H1N1 influenza pandemic (May-Sep 2009). We also included data from the pandemic and ‘post-pandemic’ winter seasons (2009-2010 and 2010-2011) to identify individuals with two confirmed HCoV infections and examine evidence for immunity against homologous reinfection. Results: We tested 1,104 swabs taken during respiratory illness and detected HCoV in 199 during the first four seasons. The rate of confirmed HCoV infection across all seasons was 390 (95% CI 338-448) per 100,000 person-weeks; highest in the Nov-Mar 2008/9 season at 674 (95%CI 537-835) per 100,000 person-weeks. The highest rate was in February at 759 (95% CI 580-975) per 100,000 person-weeks. Data collected during May-Sep 2009 showed there was small amounts of ongoing transmission, with four cases detected during this period. Eight participants had two confirmed infections, of which none had the same strain twice. Conclusion: Our results provide evidence that HCoV infection in England is most intense in winter, but that there is a small amount of ongoing transmission during summer periods. We found some evidence of immunity against homologous reinfection.

Seasonality and immunity to laboratory-confirmed seasonal coronaviruses (HCoV-NL63, HCoV-OC43, and HCoV-229E): results from the Flu Watch cohort study

Background: There is currently a pandemic caused by the novel coronavirus SARS-CoV-2. The intensity and duration of this first wave in the UK may be dependent on whether SARS-CoV-2 transmits more effectively in the winter than the summer and the UK Government response is partially built upon the assumption that those infected will develop immunity to reinfection in the short term. In this paper we examine evidence for seasonality and immunity to laboratory-confirmed seasonal coronavirus (HCoV) from a prospective cohort study in England. Methods: In this analysis of the Flu Watch cohort, we examine seasonal trends for PCR-confirmed coronavirus infections (HCoV-NL63, HCoV-OC43, and HCoV-229E) in all participants during winter seasons (2006-2007, 2007-2008, 2008-2009) and during the first wave of the 2009 H1N1 influenza pandemic (May-Sep 2009). We also included data from the pandemic and ‘post-pandemic’ winter seasons (2009-2010 and 2010-2011) to identify individuals with two confirmed HCoV infections and examine evidence for immunity against homologous reinfection. Results: We tested 1,104 swabs taken during respiratory illness and detected HCoV in 199 during the first four seasons. The rate of confirmed HCoV infection across all seasons was 390 (95% CI 338-448) per 100,000 person-weeks; highest in the Nov-Mar 2008/9 season at 674 (95%CI 537-835). The highest rate was in February at 759 (95% CI 580-975). Data collected during May-Sep 2009 showed there was small amounts of ongoing transmission, with four cases detected during this period. Eight participants had two confirmed infections, of which none had the same strain twice. Conclusion: Our results provide evidence that HCoV infection in England is most intense in winter, but that there is a small amount of ongoing transmission during summer periods. We found some evidence of immunity against homologous reinfection.

Incomplete Protection against Dengue Virus Type 2 Re-infection in Peru.

BackgroundNearly half of the world’s population is at risk for dengue, yet no licensed vaccine or anti-viral drug is currently available. Dengue is caused by any of four dengue virus serotypes (DENV-1 through DENV-4), and infection by a DENV serotype is assumed to provide life-long protection against re-infection by that serotype. We investigated the validity of this fundamental assumption during a large dengue epidemic caused by DENV-2 in Iquitos, Peru, in 2010–2011, 15 years after the first outbreak of DENV-2 in the region.Methodology/Principal FindingsWe estimated the age-dependent prevalence of serotype-specific DENV antibodies from longitudinal cohort studies conducted between 1993 and 2010. During the 2010–2011 epidemic, active dengue cases were identified through active community- and clinic-based febrile surveillance studies, and acute inapparent DENV infections were identified through contact tracing studies. Based on the age-specific prevalence of DENV-2 neutralizing antibodies, the age distribution of DENV-2 cases was markedly older than expected. Homologous protection was estimated at 35.1% (95% confidence interval: 0%–65.2%). At the individual level, pre-existing DENV-2 antibodies were associated with an incomplete reduction in the frequency of symptoms. Among dengue cases, 43% (26/66) exhibited elevated DENV-2 neutralizing antibody titers for years prior to infection, compared with 76% (13/17) of inapparent infections (age-adjusted odds ratio: 4.2; 95% confidence interval: 1.1–17.7).Conclusions/SignificanceOur data indicate that protection from homologous DENV re-infection may be incomplete in some circumstances, which provides context for the limited vaccine efficacy against DENV-2 in recent trials. Further studies are warranted to confirm this phenomenon and to evaluate the potential role of incomplete homologous protection in DENV transmission dynamics.

Vigilance to Limit the Bidirectional Introduction and Co-circulation of Virus Serotypes Aims to Reduce Risk of Severe Dengue Disease in North East India

Dengue is a serious re-emerging arboviral disease that presents a global human health challenge. Infection is caused by one of several recognised serotypes of dengue virus, a member of the mosquito-transmitted Flaviviridae family of human pathogens, which also includes yellow fever, Zika and West Nile viruses. The greatest burden of dengue is borne by countries in the Asia Pacific region, in particular South East Asia and the Indian subcontinent where infection breaks out with increasing frequency and intensity. The World Health Organization South East Asia Region has a population of 1.3 billion people and includes 11 countries, of which Thailand, Myanmar and India have the highest reported incidence of dengue. Infection outcomes vary from the commonly asymptomatic or a self-limiting fever to more severe manifestations such as dengue haemorrhagic fever and dengue shock syndrome. Although primary infection with one serotype elicits lifelong immunity against homologous reinfection, severe dengue is linked to an antibody-related immunopathological response that is triggered by secondary infection with a heterologous serotype. The principal vectors of transmission are the day-biting mosquitoes Aedes aegypti and Ae. albopictus, the respective preference of which for urban and rural habitats has facilitated the rapid and continued spread of dengue across tropical and sub-tropical climatic zones. The narrow elevated corridor of North East India was considered historically to be non-endemic for dengue and as such separated areas of high endemicity in the Bengal Delta and the other zones of India from those in Thailand and Myanmar. In these regions the predominant serotype is usually distinct, so a breach of this geographical bottleneck would potentially enable the co-circulation of virus serotypes, thus posing an increased risk of severe disease upon secondary infection. This alarming scenario may now be realized following the notification of clinical cases in the states of Arunachal Pradesh, Assam and Manipur in recent years. While incidence is still sporadic in North East India limitation of local outbreaks is required through vigilant adherence to the integrated implementation of clinical management, diagnosis, surveillance and vector control in order to prevent the transcontinental spread of dengue.

Characterization of immune responses following homologous reinfection of pigs with European subtype 1 and 3 porcine reproductive and respiratory syndrome virus strains that differ in virulence

Porcine reproductive and respiratory syndrome virus (PRRSV) causes significant economic losses to the pork industry worldwide. Vaccination results often in limited protection. Understanding host immune responses elicited by different PRRSV strains could help to develop more efficacious vaccines. In the current study we characterized immunological responses and viral kinetics in pigs after primo infection and homologous challenge of the highly virulent European subtype 3 strain Lena, and the moderate to low virulent subtype 1 strain LV. Eighteen pigs were infected per strain, and 18 non-infected pigs served as control. Post mortem analysis was performed at days 7, 46 and 60 p.i. At day 46, pigs were challenged with the homologous strain. After the first inoculation, pigs infected with Lena developed fever and clinical symptoms, while this was not observed in pigs infected with LV. Virus titres in serum were about 100-fold higher in pigs infected with Lena than in pigs infected with LV. An inflammatory response was observed in pigs after primo infection with Lena with significantly higher levels of IL-12, IL-1β and TNF-α in the bronchoalveolar lavage. IFN-γ ELISPOT assay showed comparable responses between Lena and LV. Neutralizing antibodies were detected earlier in serum of pigs infected with Lena than in pigs infected with LV. After the challenge, a boost in antibody levels in both groups was observed. Challenge infection resulted in both groups in complete protection and sterile immunity, with no viraemia, clinical symptoms or viral RNA in tissues. In conclusion, although there were clear differences in immunological, clinical and virological responses to the primo infection, there were no differences observed in protection against homologous challenge.

Does homologous reinfection drive multiple-wave influenza outbreaks? Accounting for immunodynamics in epidemiological models

Epidemiological models of influenza transmission usually assume that recovered individuals instantly develop a fully protective immunity against the infecting strain. However, recent studies have highlighted host heterogeneity in the development of this immune response, characterized by delay and even absence of protection, that could lead to homologous reinfection (HR). Here, we investigate how these immunological mechanisms at the individual level shape the epidemiological dynamics at the population level. In particular, because HR was observed during the successive waves of past pandemics, we assess its role in driving multiple-wave influenza outbreaks. We develop a novel mechanistic model accounting for host heterogeneity in the immune response. Immunological parameters are inferred by fitting our dynamical model to a two-wave influenza epidemic that occurred on the remote island of Tristan da Cunha (TdC) in 1971, and during which HR occurred in 92 of 284 islanders. We then explore the dynamics predicted by our model for various population settings. We find that our model can explain HR over both short (e.g. week) and long (e.g. month) time-scales, as reported during past pandemics. In particular, our results reveal that the HR wave on TdC was a natural consequence of the exceptional contact configuration and high susceptibility of this small and isolated community. By contrast, in larger, less mixed and partially protected populations, HR alone cannot generate multiple-wave outbreaks. However, in the latter case, we find that a significant proportion of infected hosts would remain unprotected at the end of the pandemic season and should therefore benefit from vaccination. Crucially, we show that failing to account for these unprotected individuals can lead to large underestimation of the magnitude of the first post-pandemic season. These results are relevant in the context of the 2009 A/H1N1 influenza post-pandemic era.

Molecular and epidemiological characterization of Plasmodium vivax recurrent infections in southern Mexico

BackgroundIn southern Mexico, malaria transmission is low, seasonal, and persistent. Because many patients are affected by two or more malaria episodes caused by Plasmodium vivax, we carried out a study to determine the timing, frequency, and genetic identity of recurrent malaria episodes in the region between 1998 and 2008.MethodsSymptomatic patients with more than one P. vivax infection were followed up, and blood samples were collected from primary and recurrent infections. DNA extracted from infected blood samples was analyzed for restriction fragment length polymorphism (RFLP) in genes encoding csp and msp3α, as well as size variation in seven microsatellites.ResultsOne hundred and forty six parasite samples were collected from 70 patients; of these, 65 patients had one recurrent infection, four had two, and one had three recurrent infections. The majority of recurrent infections occurred within one year of the primary infection, some of which were genetically homologous to the primary infection. As the genetic diversity in the background population was high, the probability of homologous re-infection was low and the homologous recurrences likely reflected relapses. These homologous recurrent infections generally had short (< 6 months) or long (6–12 months) intervals between the primary (PI) and recurrent (RI) infections; whereas infections containing heterologous genotypes had relatively longer intervals. The epidemiological data indicate that heterologous recurrences could be either relapse or re-infections.ConclusionsGenetic and temporal analysis of P. vivax recurrence patterns in southern Mexico indicated that relapses play an important role in initiating malaria transmission each season. The manifestation of these infections during the active transmission season allowed the propagation of diverse hypnozoite genotypes. Both short- and long-interval relapses have contributed to parasite persistence and must be considered as targets of treatment for malaria elimination programs in the region to be successful.

T cell reactions of Eimeria bovis primary- and challenge-infected calves

Eimeria bovis infections commonly have clinical impact only on young animals, as homologous reinfections generally are under immunological control. So far, the nature of the immune responses delivering protection to calves has not been investigated. In this study we therefore analysed local and peripheral proliferative T cell activities of primary and challenge-infected calves and investigated the occurrence of T cell phenotypes in the peripheral blood and in mucosal gut segments isolated either by bioptic means or by necropsies.We show that lymphocytes of E. bovis-infected calves exhibit effective, transient antigen-specific proliferative responses in the course of prepatency of primary infection but fail to react after homologous reinfection suggesting early abrogation of parasite development. Whilst in primary infection an expansion of peripheral CD4+ T cells was observed, reinfection had no effect on the proportions of CD4+, CD8+ subsets or gammadeltaTCR+ T cells. In contrast, both E. bovis primary and challenge infections had an impact on local tissue T cell distribution. Primary infection was characterised by a CD4+ T cell infiltration early in prepatency in ileum and later in colon mucosa, whereas CD8+ T cells were only found accumulating in the latter gut segment. Challenge infection led to infiltration of both CD4+ and CD8+ T cells in small intestine and large intestine segments indicating protective functions of both cell types. In contrast, infiltration of ileum and colon mucosa with gammadeltaTCR+ T cells was restricted to primary infection.

Artemether Treatment of Prepatent Schistosoma japonicum Induces Resistance to Reinfection in Association with Reduced Pathology

Artemether (ART) is a well-described antimalarial with efficacy against juvenile schistosomes, with 7-day-old schistosomula being particularly susceptible. Both ART-affected worms and parasites developing from irradiated cercariae die at similar times after infection. Our aim was to determine if ART treatment of prepatent schistosomiasis japonica may result in the generation of a protective immune response. Female CBA mice were treated with a single dose of ART at defined time points after percutaneous infection with a virulent Chinese mainland strain of Schistosoma japonicum. Half of the mouse cohorts were subjected to homologous parasite strain reinfection after drug treatment to assess protective effects of ART therapy. Two independent trials demonstrated that a statistically significant (58% and 50%) reduction in challenge worm burden occurred after reinfection of those mice treated with ART at two weeks p.i. A reduction in the IL-4 response to soluble worm antigen preparation (SWAP) was also seen in ART-treated mice but with no correlation to reinfection resistance. In the Chinese mainland strain used, ART treatment of prepatent infection at the appropriate time point induced resistance to reinfection. There was also an anti-pathology effect observed in ART-treated mice that remained significant after reinfection.

Experimental infection of macaques with human metapneumovirus induces transient protective immunity

Human metapneumovirus (hMPV), a member of the family Paramyxoviridae, is a causative agent of acute respiratory-tract illness. Two main hMPV lineages circulate worldwide and reinfections occur frequently. It is unclear what level of protection is induced by natural hMPV infection, what the durability of this protection is and whether it differs for reinfection with homologous or heterologous viruses. Here, protective immunity in cynomolgus macaques at different time points after inoculation with molecularly cloned prototype viruses of the two main lineages of hMPV has been addressed. Animals received a homologous challenge at 4, 6 or 12 weeks after the primary infection. In addition, animals that had been inoculated three times within 10 weeks were challenged with homologous or heterologous virus 8 months later. Primary infection with 10(7) TCID(50) resulted in virus shedding and induction of virus-neutralizing antibody responses, with higher titres against the homologous than the heterologous virus. Infections associated with virus shedding and seroconversion protected completely from homologous reinfection within 6 weeks, and partly at 12 weeks, after primary infection. Eight months later, protection had waned to virtually undetectable levels. This study demonstrates that experimental hMPV infection induces transient protective immunity.

Plasmodium yoelii: Influence of antimalarial treatment on acquisition of immunity in BALB/c and DBA/2 mice

The effect of antimalarial drugs on immune responses to the malaria infection is evaluated in vivo using two experimental self-cured rodent models. BALB/c and DBA/2 mice were infected by Plasmodium yoelii 17XNL and 17XL strains, respectively, and then treated with different doses of antimalarial drugs: chloroquine (228 mg/kg or 114 mg/kg of the body weight) or artesunate (78 mg/kg or 39 mg/kg). The effect of antimalarial drugs on host immune responses was evaluated by parasitemia, splenocyte IFN-γ production level, and parasite-specific IgG level in the serum, however, no significant differences were observed between drug-treated and untreated groups. Moreover, most of the infected mice of all groups showed the ability to resist homologous reinfection (challenged on day 60 post-infection), only a few mice experienced transient, low parasitemia. The rechallenged mice were accompanied by high level of parasite-specific IgG. Therefore, this research implicated that, for BALB/c and DBA/2 mice, chloroquine or artesunate treatment of blood-stage P. yoelii infections does not compromise acquired immunity to malaria in either primary infection or upon rechallenge.

Leishmania infantum-induced primary and challenge infections in rhesus monkeys ( Macaca mulatta): a primate model for visceral leishmaniasis

Visceral leishmaniasis (VL) was experimentally induced in rhesus macaques (Macaca mulatta) by intravenously inoculating 2 x 10(7)amastigotes/kg of body weight of Leishmania infantum. The macaques developed a systemic disease showing characteristic features of human VL such as fever, diarrhoea, body weight loss, anaemia, hypergammaglobulinaemia and transient lymphocytosis, as well as lymph node, liver and/or spleen enlargement. Nine weeks after infection, one primate showed pronounced weight loss, became moribund and was euthanized. The necropsy findings included granulomas composed of parasite-containing macrophages, lymphocytes and plasma cells in the liver, spleen and lymph nodes. The remaining macaques had a sustained course of infection but developed a mild-to-moderate illness that subsequently showed evidence of self-cure. Of note, pathological findings included a typical cell-mediated immunity-induced granulomatous reaction that had an effect on the control of parasite replication. All infected monkeys responded with increased production of anti-Leishmania-specific IgG antibodies. Despite the fact that clinical resistance to L. infantum was not consistently associated with a parasite-specific cell-mediated immune response, drug-cured macaques from the primary infection acquired immunity to homologous re-infection. These findings point to the feasibility of using the L. infantum macaque model for pre-clinical evaluation of novel chemotherapeutics or vaccine candidates for human VL.

GM-CSF transgene-based adjuvant allows the establishment of protective mucosal immunity following vaccination with inactivated Chlamydia trachomatis.

Cellular and humoral immune responses induced following murine Chlamydia trachomatis infection confer almost sterile protection against homologous reinfection. On the other hand, immunization with inactivated organism induces little protective immunity in this model system. The underlying mechanism(s) that determines such divergent outcome remains unclear, but elucidating the mechanism will probably be important for chlamydial vaccine development. One of the distinct differences between the two forms of immunization is that chlamydia replication in epithelial cells causes the secretion of a variety of proinflammatory cytokines and chemokines, such as GM-CSF, that may mobilize and mature dendritic cells and thereby enhance the induction of protective immunity. Using a murine model of C. trachomatis mouse pneumonitis lung infection and intrapulmonary adenoviral GM-CSF transfection, we demonstrate that the expression of GM-CSF in the airway compartment significantly enhanced systemic Th1 cellular and local IgA immune responses following immunization with inactivated organisms. Importantly, immunized mice had significantly reduced growth of chlamydia and exhibited less severe pulmonary inflammation following challenge infection. The site of GM-CSF transfection proved important, since mice immunized with inactivated organisms after GM-CSF gene transfer by the i.p. route exhibited little protection against pulmonary challenge, although i.p. immunization generated significant levels of systemic Th1 immune responses. The obvious difference between i.p. and intrapulmonary immunization was the absence of lung IgA responses following i.p. vaccination. In aggregate, the findings demonstrate that the local cytokine environment is critical to the induction of protective immunity following chlamydial vaccination and that GM-CSF may be a useful adjuvant for a chlamydial vaccine.

Plasmodium chabaudi chabaudi: Effect of Low Parasitemias on Immunity in CB6F1 Mice

Favila-Castillo, L., Monroy-Ostria, A., and Garcia-Tapia, D. 1999.Plasmodium chabaudi chabaudi: Effect of low parasitemias on immunity in CB6F1 mice.Experimental Parasitology92,73–80. We examined the effect that low parasitemias have on the immune response of CB6F1 mice infected withPlasmodium chabaudi chabaudiAS. Ascending parasitemias were stopped by chloroquine treatment when they were between 1.6 and 9.4%. Mice that suffered low parasitemias developed good immunity to homologous reinfection but, contrary to what happened in mice that suffered full parasitemias, they did not develop immunity to heterologous reinfection withPlasmodium yoelii17XL. Total IgG antiparasite antibody responses were similar in mice that suffered low or full parasitemia, both in primary infection and after reinfection. At the level of isotypes, IgM, IgG1, IgG2b, and IgG3 responses were similar in mice that suffered low or full parasitemias, but after reinfection, mice that suffered low parasitemias responded with higher levels of IgG2a than mice that suffered full parasitemias. Mice that suffered low parasitemias did not have splenomegaly but their immunity to homologous reinfection was diminished after splenectomy in a manner similar to that of splenectomized mice that suffered full parasitemia. CB6F1 mice can develop homologous immunity even if exposed to low parasitemias but cannot develop heterologous immunity unless exposed to high parasite loads.