Opisthorchis viverrini: influence of maternal infection in hamsters on offspring infected with homologous parasite and their IgG antibody response

We investigated the influence in hamsters of a maternal Opisthorchis viverrini infection on their offspring infected with homologous parasites and the kinetics of the O. viverrini-specific IgG antibody responses. No significant difference (P > 0.05) was found in the specific IgG antibody response and the number of O. viverrini eggs per gram feces (EPG) between infected offspring from infected mothers and infected offspring from uninfected mothers. A significant difference (P < 0.05) of EPG per worm was found between infected offspring from infected mothers and infected offspring from uninfected mothers only when the offspring were infected with O. viverrini after weaning at 5 weeks of age. The worm loads in infected offspring from infected mothers were significantly less than that in infected offspring from uninfected mothers. This study demonstrated that maternal infection effects worm fecundity and the worm load in an infected offspring.     

Transgenerational effect of infection in Plasmodium-infected mosquitoes

Transgenerational effects of infection have a huge potential to influence the prevalence and intensity of infections in vectors and, by extension, disease epidemiology. These transgenerational effects may increase the fitness of offspring through the transfer of protective immune factors. Alternatively, however, infected mothers may transfer the costs of infection to their offspring. Although transgenerational immune protection has been described in a dozen invertebrate species, we still lack a complete picture of the incidence and importance of transgenerational effects of infection in most invertebrate groups. The existence of transgenerational infection effects in mosquito vectors is of particular interest because of their potential for influencing parasite prevalence and intensity and, by extension, disease transmission. Here we present what we believe to be the first study on transgenerational infection effects in a mosquito vector infected with malaria parasites. The aim of this experiment was to quantify both the benefits and the costs of having an infected mother. We find no evidence of transgenerational protection in response to a Plasmodium infection. Having an infected mother does, however, entail considerable fecundity costs for the offspring: fecundity loss is three times higher in infected offspring issued from infected mothers than in infected offspring issued from uninfected mothers. We discuss the implications of our results and we call for more studies looking at transgenerational effects of infection in disease vectors.     

Influence of maternal infection on offspring resistance towards parasites

Immunoglobulins, parasite circulating antigens, immune cells, cytokines and other cell-related products can be transferred from infected mothers to their young. They can combine their effects to interact with the invading parasites, as well as to induce a long-term modulation of the offspring's capacity to mount an immune response to subsequent exposure to parasites. The protective effect of maternally derived antibodies may be limited by the selective transfer of immunoglobulin isotypes. Maternal antibodies may also prevent the priming of specific cells in offspring or inhibit the progeny's antibody production by interacting with B-cell receptors or with the idiotypic repertoire. The potentially beneficial priming effect of transferred parasitic antigens may be altered by the Th2-cell-biased foetal environment and such antigens may also induce deletion or anergy of T- and B-cell clones in offspring. Therefore, besides protective effects, maternal infection may downregulate the offspring's immune response. If such hyporesponsiveness may be clearly harmful (in increasing the risk or in worsening congenital or postnatally acquired infections in offspring), it can also be beneficial (in limiting the pathogenesis of some infections). Here, Yves Carlier and Carine Truyens review the rationale of these complex foeto-maternal relationships in parasitic diseases.     

Long-term maternal effect on offspring immune response in song sparrows Melospiza melodia

Knowledge of the causes of variation in host immunity to parasitic infection and the time-scales over which variation persists, is integral to predicting the evolutionary and epidemiological consequences of host-parasite interactions. It is clear that offspring immunity can be influenced by parental immune experience, for example, reflecting transfer of antibodies from mothers to young offspring. However, it is less clear whether such parental effects persist or have functional consequences over longer time-scales, linking a parent's previous immune experience to future immune responsiveness in fully grown offspring. We used free-living song sparrows (Melospiza melodia) to quantify long-term effects of parental immune experience on offspring immune response. We experimentally vaccinated parents with a novel antigen and tested whether parental vaccination influenced the humoral antibody response mounted by fully grown offspring hatched the following year. Parental vaccination did not influence offspring baseline antibody titres. However, offspring of vaccinated mothers mounted substantially stronger antibody responses than offspring of unvaccinated mothers. Antibody responses did not differ between offspring of vaccinated and unvaccinated fathers. These data demonstrate substantial long-term effects of maternal immune experience on the humoral immune response of fully grown offspring in free-living birds.     

Transmission of experimentally-induced rat virus infection

The duration of transmission of rat virus (RV) infection was determined using Sprague-Dawley rats inoculated oronasally as juveniles (4 weeks old) or as infants (2 days old). Contact transmission from rats inoculated as juveniles was detected for 3 weeks, whereas transmission from rats inoculated as infants occurred for 10 weeks. Transmission continued for at least 7 weeks after seroconversion occurred in rats inoculated as infants. Two of three rats that had ceased to transmit infection harbored infectious virus as detected by explantation of kidney. Intrauterine transmission occurred only after pregnant dams were inoculated with large doses of virus and was more efficient when virus was inoculated intravenously than by the oronasal route. Enzyme immunoassay antibody titers to RV in offspring of previously infected dams decreased steadily during the first 13 weeks of life and 27 of 29 offspring tested by immunofluorescence assay at 12 or 13 weeks of age were seronegative. These results indicate that RV was transmitted by rats inoculated as infants for long periods after seroconversion occurred. They also suggest that the offspring of previously-infected dams were not infected. In utero transmission of RV-Y is unlikely to occur after oronasal inoculation unless rats are exposed to large doses of virus.     

Maternal infection and fever during late gestation are associated with altered synaptic transmission in the hippocampus of juvenile offspring rats

Prenatal exposure to infection is known to affect brain development and has been linked to increased risk for schizophrenia. The goal of this study was to investigate whether maternal infection and associated fever near term disrupts synaptic transmission in the hippocampus of the offspring. We used LPS to mimic bacterial infection and trigger the maternal inflammatory response in near-term rats. LPS was administered to rats on embryonic days 15 and 16 and hippocampal synaptic transmission was evaluated in the offspring on postnatal days 20-25. Only offspring from rats that showed a fever in response to LPS were tested. Schaffer collateral-evoked field excitatory postsynaptic potentials (fEPSPs) and fiber volleys in CA1 of hippocampal slices appeared smaller in offspring from the LPS group compared with controls, but, when the fEPSPs were normalized to the amplitude of fiber volleys, they were larger in the LPS group. In addition, intrinsic excitability of CA1 pyramidal neurons was heightened, as antidromic field responses in the LPS group were greater than those from control. Short-, but not long-term plasticity was impaired since paired-pulse facilitation of the fEPSP was attenuated in the LPS group, whereas no differences in long-term potentiation were noted. These results suggest that LPS-induced inflammation during pregnancy produces in the offspring a reduction in presynaptic input to CA1 with compensatory enhancements in postsynaptic glutamatergic response and pyramidal cell excitability. Neurodevelopmental disruption triggered by prenatal infection can have profound effects on hippocampal synaptic transmission, likely contributing to the memory and cognitive deficits observed in schizophrenia.     

Maternal infection: window on neuroimmune interactions in fetal brain development and mental illness

Direct viral infection of the developing brain can have disastrous consequences for the fetus. More subtle and perhaps more insidious are viral infections of the pregnant mother, which can have long-lasting effects such as an increased risk of schizophrenia in the offspring. A recent mouse model has shown that respiratory infection in the pregnant mother leads to marked behavioral and pharmacological abnormalities in the offspring, some of which are relevant for schizophrenia and autism. This effect on fetal brain development might be caused by the maternal antiviral immune response, possibly mediated by cytokines.     

Dynamic antibody specificities and virion concentrations in circulating immune complexes in acute to chronic HIV-1 infection

Understanding the interactions between human immunodeficiency virus type 1 (HIV-1) virions and antibodies (Ab) produced during acute HIV-1 infection (AHI) is critical for defining antibody antiviral capabilities. Antibodies that bind virions may prevent transmission by neutralization of virus or mechanically prevent HIV-1 migration through mucosal layers. In this study, we quantified circulating HIV-1 virion-immune complexes (ICs), present in approximately 90% of AHI subjects, and compared the levels and antibody specificity to those in chronic infection. Circulating HIV-1 virions coated with IgG (immune complexes) were in significantly lower levels relative to the viral load in acute infection than in chronic HIV-1 infection. The specificities of the antibodies in the immune complexes differed between acute and chronic infection (anti-gp41 Ab in acute infection and anti-gp120 in chronic infection), potentially suggesting different roles in immunopathogenesis for complexes arising at different stages of infection. We also determined the ability of circulating IgG from AHI to bind infectious versus noninfectious virions. Similar to a nonneutralizing anti-gp41 monoclonal antibody (MAb), purified plasma IgG from acute HIV-1 subjects bound both infectious and noninfectious virions. This was in contrast to the neutralizing antibody 2G12 MAb that bound predominantly infectious virions. Moreover, the initial antibody response captured acute HIV-1 virions without selection for different HIV-1 envelope sequences. In total, this study demonstrates that the composition of immune complexes are dynamic over the course of HIV-1 infection and are comprised initially of antibodies that nonselectively opsonize both infectious and noninfectious virions, likely contributing to the lack of efficacy of the antibody response during acute infection.     

Respiratory syncytial virus infection in anti-mu-treated mice.

BALB/c mice were depleted of B cells by anti-mu treatment to investigate the pathogenesis of respiratory syncytial virus (RSV) infection in the absence of antibody. Termination of RSV replication after primary infection occurred with the same kinetics in anti-mu-treated mice as in phosphate-buffered saline (PBS)-treated controls. Yet, when rechallenged, anti-mu-treated mice were more permissive to RSV replication than PBS-treated controls. Anti-mu-treated mice also experienced greater illness than PBS-treated controls during both primary infection and rechallenge. Passive transfer of RSV-specific immune serum to anti-mu-treated mice before rechallenge reconstituted complete protection from RSV replication and diminished illness. Thus, RSV-specific antibody is not required to terminate RSV replication in primary infection, but without antibody, only partial immunity against rechallenge is induced. While it is unknown whether the mechanism is a direct effect on RSV titer or modulation of the illness-causing cellular immune response, the presence of RSV-specific antibody reduces illness in both primary RSV infection and rechallenge of mice.     

Maternally derived anti-helminth antibodies predict offspring survival in a wild mammal

The transfer of antibodies from mother to offspring provides crucial protection against infection to offspring during early life in humans and domestic and laboratory animals. However, few studies have tested the consequences of variation in maternal antibody transfer for offspring fitness in the wild. Further, separating the immunoprotective effects of antibodies from their association with nutritional resources provided by mothers is difficult. Here, we measured plasma levels of total and parasite-specific antibodies in neonatal (less than 10 days old) wild Soay sheep over 25 years to quantify variation in maternal antibody transfer and test its association with offspring survival. Maternal antibody transfer was predicted by maternal age and previous antibody responses, and was consistent within mothers across years. Neonatal total IgG antibody levels were positively related to early growth, suggesting they reflected nutritional transfer. Neonatal parasite-specific IgG levels positively predicted first-year survival, independent of lamb weight, total IgG levels and subsequent lamb parasite-specific antibody levels. This relationship was partly mediated via an indirect negative association with parasite burden. We show that among-female variation in maternal antibody transfer can have long-term effects on offspring growth, parasite burden and fitness in the wild, and is likely to impact naturally occurring host–parasite dynamics.     

Initial levels of maternally derived antibodies predict persistence time in offspring circulation

Vertebrate mothers transmit antibodies to offspring that provide humoral immunity early in life. The duration of protection provided by maternal antibodies varies considerably among species and has not been widely examined in birds. Determination of the length of maternal protection can be a useful predictor of when young are most likely to be susceptible to infection. The duration of maternal antibody protection was determined in Japanese Quail (Coturnix japonica) by immunizing females with keyhole limpet hemocyanin (KLH) and then collecting blood samples from offspring. Maternal antibodies remained detectable in offspring circulation for an average of 14 days (range 3–28). The duration of persistence was predicted by antibody levels as measured in maternal circulation, within egg yolks, or measured in offspring shortly after hatch. Thus, the primary benefit to offspring of high concentrations of maternal antibodies is likely to be an extended period of maternal protection during early growth and development.     

Adaptive immune defense prevents Bartonella persistence upon trans-placental transmission

Vertical transmission of Bartonella infection has been reported for several mammalian species including mice and humans. Accordingly, it is commonly held that acquired immunological tolerance contributes critically to the high prevalence of Bartonellae in wild-ranging rodent populations. Here we studied an experimental model of Bartonella infection in mice to assess the impact of maternal and newborn immune defense on vertical transmission and bacterial persistence in the offspring, respectively. Congenital infection was frequently observed in B cell-deficient mothers but not in immunocompetent dams, which correlated with a rapid onset of an antibacterial antibody response in infected WT animals. Intriguingly, B cell-deficient offspring with congenital infection exhibited long-term bacteremia whereas B cell-sufficient offspring cleared bacteremia within a few weeks after birth. Clearance of congenital Bartonella infection resulted in immunity against bacterial rechallenge, with the animals mounting Bartonella-neutralizing antibody responses of normal magnitude. These observations reveal a key role for humoral immune defense by the mother and offspring in preventing and eliminating vertical transmission. Moreover, congenital Bartonella infection does not induce humoral immune tolerance but results in anti-bacterial immunity, questioning the contribution of neonatal tolerance to Bartonella prevalence in wild-ranging rodents.     

Prehatching maternal investment and offspring immunity in the pied flycatcher (Ficedula hypoleuca)

Maternal investment in offspring immunity via egg quality may be an adaptive evolutionary strategy shaped by natural selection. We investigated how maternal investment in eggs can influence offspring immunity by conducting two experiments. First, we manipulated foraging performance of the mothers before egg laying by attaching a small weight to their back feathers. During the nestling period, we investigated offspring total antibody production at the age of 7 days and after antibody challenge, and conducted a partial cross-fostering design to separate the effects of the experiment and rearing-related variation on offspring immunity. In a separate experiment, partial cross-fostering with antibody challenging without female pied flycatcher manipulation was conducted for another set of nests. Total antibody levels at the age of 7 days were reduced in nestlings of the experimental female pied flycatchers when compared with the set of unmanipulated nests. Maternal investment in the eggs may affect some aspects of offspring immunity during the early nestling period and this investment is costly. However, antibody response to a set of novel antigens (sheep red blood cells) at the end of the nestling period was not affected by the female pied flycatchers treatment. Instead our results suggest that general antibody responsiveness is mainly determined by the rearing environment and total antibody levels before the injection.     

Maternal infection and immune involvement in autism

Recent studies have highlighted a connection between infection during pregnancy and the increased risk of autism in the offspring. Parallel studies of cerebral spinal fluid, blood and postmortem brains reveal an ongoing, hyper-responsive inflammatory-like state in many young as well as adult autism subjects. There are also indications of gastrointestinal problems in at least a subset of autistic children. Work on the maternal infection risk factor using animal models indicates that aspects of brain and peripheral immune dysregulation can begin during fetal development and continue through adulthood. The offspring of infected or immune-activated dams also display cardinal behavioral features of autism, as well as neuropathology consistent with that seen in human autism. These rodent models are proving useful for the study of pathogenesis and gene-environment interactions as well as for the exploration of potential therapeutic strategies.     

Antibody responses induced by SHIV infection are more focused than those induced by soluble native HIV-1 envelope trimers in non-human primates

The development of an effective human immunodeficiency virus (HIV-1) vaccine is a high global health priority. Soluble native-like HIV-1 envelope glycoprotein trimers (Env), including those based on the SOSIP design, have shown promise as vaccine candidates by inducing neutralizing antibody responses against the autologous virus in animal models. However, to overcome HIV-1’s extreme diversity a vaccine needs to induce broadly neutralizing antibodies (bNAbs). Such bNAbs can protect non-human primates (NHPs) and humans from infection. The prototypic BG505 SOSIP.664 immunogen is based on the BG505 env sequence isolated from an HIV-1-infected infant from Kenya who developed a bNAb response. Studying bNAb development during natural HIV-1 infection can inform vaccine design, however, it is unclear to what extent vaccine-induced antibody responses to Env are comparable to those induced by natural infection. Here, we compared Env antibody responses in BG505 SOSIP-immunized NHPs with those in BG505 SHIV-infected NHPs, by analyzing monoclonal antibodies (mAbs). We observed three major differences between BG505 SOSIP immunization and BG505 SHIV infection. First, SHIV infection resulted in more clonal expansion and less antibody diversity compared to SOSIP immunization, likely because of higher and/or prolonged antigenic stimulation and increased antigen diversity during infection. Second, while we retrieved comparatively fewer neutralizing mAbs (NAbs) from SOSIP-immunized animals, these NAbs targeted more diverse epitopes compared to NAbs from SHIV-infected animals. However, none of the NAbs, either elicited by vaccination or infection, showed any breadth. Finally, SOSIP immunization elicited antibodies against the base of the trimer, while infection did not, consistent with the base being placed onto the virus membrane in the latter setting. Together these data provide new insights into the antibody response against BG505 Env during infection and immunization and limitations that need to be overcome to induce better responses after vaccination.     

Temporal effects of gamma interferon deficiency on the course of Friend retrovirus infection in mice

The current studies demonstrate complex and seemingly contradictory effects by gamma interferon (IFN-gamma) on Friend virus (FV) infection. Both temporal and tissue-specific effects were observed. During the first week of infection, IFN-gamma-deficiency caused increased levels of FV infection in multiple tissues. Surprisingly, however, by 2 weeks postinfection, IFN-gamma-deficient mice had significantly lower levels of infection in both the spleen and bone marrow compared to wild-type mice. The rapid reduction of virus in the IFN-gamma-deficient mice correlated with a more rapid virus-neutralizing antibody response than was observed in the wild-type mice. Furthermore, the virus-neutralizing antibody response in wild-type mice could be accelerated by ablation of their IFN-gamma response. Although the IFN-gamma-deficient mice developed an accelerated virus-neutralizing antibody response, they did not class-switch to immunoglobulin G class immunoglobulins nor could they maintain long-term virus-neutralizing antibody titers. Eventually, all of the IFN-gamma-deficient mice failed to keep persistent virus in check and developed fatal FV-induced erythroleukemia.     

Neutralizing antibody responses to HIV-1 infection

Neutralizing antibodies represent an important component of immune control in many viral infections. In HIV-1 infection, almost all individuals develop antibodies capable of neutralizing autologous viruses in vitro; however, the role of these antibodies in vivo still remains unclear. Their absence during the acute phase of infection, when the viral levels are brought under control, suggests they play a minor role in immune control and that cellular immune responses are more critical during this time. However, during chronic infection these antibodies may be important in preventing cell-to-cell spread and they still represent our best hope of providing sterilizing immunity (i.e., prevention of infection) by vaccination. Significant advances over the last few years in understanding the structure of the envelope glycoproteins have renewed interest in the role of neutralizing antibodies and the possibility that immunogens capable of stimulating a neutralizing antibody response can be developed.     

Brugia pahangi: effects of maternal filariasis on the responses of their progeny to homologous challenge infection.

Granulomatous lesion formation and immune responses to Brugia pahangi infections were compared in age-matched male progeny of homologously infected and uninfected female jirds. Infections initiated in 2-week-old offspring yielded mean +/- SD adult worm recoveries of 6.0 +/- 5.7 and 4.2 +/- 5.4 in offspring from infected or uninfected mothers, respectively. Infections initiated in 4-week-old offspring resulted in an mean +/- SD recovery of adult worms of 11.3 +/- 11.3 and 10.2 +/- 5.8 in offspring from infected and uninfected mothers, respectively. The ratio of intralymphatic thrombi per intralymphatic worm was similar between infected offspring from infected or uninfected mothers within experiments. Areas of granulomas around B. pahangi antigen-coated beads embolized in the lungs were not significantly affected by maternal origin in infected or uninfected progeny. Offspring infected at 2 or 4 weeks of age from infected mothers exhibited significantly reduced titers of serum IgG antibodies to Brugia antigens at 5-8 weeks postinfection compared to infected offspring of uninfected mothers. Infected offspring from infected mothers also had significantly fewer splenic IgG plaque-forming cells to B. pahangi antigens at 5 weeks postinfection than similarly infected offspring from uninfected mothers. Western immunoblot analysis indicated qualitative and quantitative reductions in serum antibody reactivity to adult B. pahangi antigens in infected progeny of infected females compared to age-matched infected controls. Reduced homologous serum antibody responses in progeny exposed to maternal B. pahangi infection suggest that maternal immunoregulation to filarial antigens may occur. Reduced antibody responsiveness to B. pahangi antigens observed in infected offspring from infected mothers, however, had no demonstrable effect on adult worm burdens, microfilaremias, lymphatic lesion formation, or antigen-specific granulomatous inflammatory responses compared to infected progeny of uninfected mothers.     

Immune responses to a soluble schistosomal egg antigen preparation during chronic primary infection with Schistosoma mansoni.

Murine schistosomiasis mansoni is characterized by an intense, predominantly cell-mediated, anti-egg, granulomatous response to schistosomal egg antigens (SEA). Anti-SEA responses include lymphocyte blastogenesis, the production of the lymphokine eosinophil stimulation promoter (ESP), hemagglutinating antibody, heat-labile and heat-stable, 72-hr passive cutaneous anaphylaxis (PCA) antibodies, and pronounced peripheral blood eosinophilia. These responses were followed during the course of chronic (1 year) infection and analyzed with specific reference to the observed diminution of granuloma formation, in the presence of continued antigenic exposure, which occurs by 10 to 12 weeks after infection and persists during long-term schistosomiasis. Lymphocyte blastogenesis and peripheral blood eosinophilia were positive from the 8th week of infection until the 50th. Lymphokine production and circulating heat-labile PCA antibody were only positive for a few weeks after 8 weeks of infection. In contrast, hemagglutinating antibody and heat-stable, 72-hr PCA antibody increased during weeks 10 to 14 and remained high throughout chronic infection. The development and regression of these various immune responses to SEA indicate that there are several potential mechanisms that could explain the immunoregulatory interactions that result in specifically diminished lesion formation in this chronic infection.     

Episodic occurrence of antibodies against the bovine leukemia virus Rex protein during the course of infection in sheep.

Infection by bovine leukemia virus (BLV) is characterized by a long clinical latency after which some individuals develop B-cell tumors. The contributions of the viral regulatory proteins Tax and Rex during clinical latency and disease are incompletely understood. To learn about Rex expression in the host, we used a sensitive immunoprecipitation assay to detect Rex antibodies throughout the course of BLV infection in sheep. Sixty percent of the infected animals produced Rex antibodies in intermittent episodes. This pattern differed markedly from that of antibodies to virion structural proteins, which were maintained in all animals throughout infection. Only one of two animals that developed tumors had detectable Rex antibodies at the time, although the other had previously demonstrated an especially strong Rex antibody response. We examined the Rex response in the context of BLV infection by comparing it with the frequency of circulating mononuclear blood cells that could transcribe BLV RNA or produce infectious virus. Episodes of Rex antibody occurrence followed some but not all increases in the number of BLV-transcribing cells. Since the appearance of circulating antibodies requires that the intracellular Rex protein be available to serve as antigen, the episodic pattern of occurrence of Rex antibodies could result from intermittent killing by virus-specific cytotoxic cells. Fluctuations in titer that were observed during some episodes of Rex response could be due to antibody retention by antigen present in lymphoid tissue.