Altered Offspring Immunity in Maternal Parasitic Infections

During pregnancy, the maternal immune system must make precise and balanced changes to both support the life of the fetus and protect the mother and fetus from infection (1). When this balance is disrupted, such as during maternal infection, offspring development can be impeded and offspring immunity negatively impacted throughout their life (2). More specifically, dysregulation of the cytokine milieu in the placenta is thought to contribute to miscarriage and preterm birth (3), as a careful cytokine balance is needed to maintain homeostasis and promote fetal survival (4). Although there has been a renewed interest in the field of maternal infection, the majority of studies focus on viral and bacterial infections. This has led to a gap in knowledge of the effects of maternal parasitic infection on offspring development and immunity, even though there has been evidence of immunomodulation due to maternal parasitic infections since the late 1960s (5).

Millions of women are at risk for parasitic infection; an estimated 668 million women of reproductive age are currently at risk for infection by soil-transmitted helminths (6) and ∼30 million pregnancies occur in malaria-endemic areas per year (7). These endemic regions also have increased rates of infant mortality and death before 5 y of age (8). Although many variables can impact childhood mortality rates, such as access to clean water, literacy of parents, and gross national income (8, 9), maternal parasitic infections have been implicated in increasing the risk of preterm delivery (10, 11), stillbirth (11, 12), and spontaneous abortion (13, 14). Additional studies measuring immune cell and cytokine frequencies have found evidence of immune sensitization in cord blood (15, 16), decreased vaccine efficacy (17–19), and increased susceptibility to secondary parasitic infection (20, 21). Currently, there is no clear mechanistic understanding of how maternal infection causes long-lived changes to offspring immunity, but this brief review of altered offspring immunity as a consequence of maternal parasitic infection hopes to expose similarities in offspring immunity between select maternal parasitic infection models. The models chosen for this review represent the classes of parasites with the largest body of epidemiological literature on maternal infections, with hopes of elucidating a mechanistic understanding of how maternal inflammation impacts offspring immunity.

Protozoa are one-celled parasitic eukaryotes (22) that cause more than a million deaths annually (23). Maternal infections with protozoa, such as malaria, leishmaniasis, and toxoplasmosis, can manifest as congenital infections due to vertical transmission from mother to offspring either in utero or during delivery (24). Protozoan infections during pregnancy generally cause low birth weight, with an increased risk of spontaneous abortion and stillbirth. In terms of offspring immunity, maternal protozoan infections can reduce offspring immunity by decreasing the functionality of subsets of T cells by downregulating the production of IFN-γ, causing a Th2 response bias (25). The rate of transmission from maternal infection to congenital protozoan infection is currently unclear. Studies in placental malaria, in which Plasmodium-infected RBCs accumulate in the placental intervillous space (26), have shown that the rate of congenital malaria, or when infected RBCs infiltrate the cord blood, can range from 3% of malaria-infected mothers to 34%, depending on pregnancy trimester, geographic region, parasitemia of the mother, and Plasmodium strain (27–29), making it unclear how many children are actually affected by congenital malaria. Meanwhile, the risk for congenital toxoplasmosis increases as pregnancy progresses from 2% up to 54% (30), whereas the rate of transmission in canine leishmaniasis can be as high as 72% (31). Conversion from maternal or placental infection to congenital infection is thought to be partially modulated by maternal factors, such as maternal to fetal cell transfer and increased blood circulation (27, 28), but the heterogeneity of transmission and conversion rate makes it difficult to determine what factors specifically modulate this transmission.

Malaria, the protozoa with the most significant impact on humans (32), is mosquito-borne and often causes cyclic flulike symptoms (33). Although there are drug treatment options against malaria, they have lost efficacy over time (34) and many drugs are not recommended to be taken during the first trimester of pregnancy (35). Together, in conjunction with limited testing and treatment resources (36), malaria infection during pregnancy, or maternal malaria, affects ∼25% of pregnancies in malaria-endemic areas (37). During pregnancy, malaria infection is known to cause higher rates of miscarriage, preterm delivery, low birth weight, and neonatal death (11). Congenital malaria can either be spontaneously cleared from the newborn or convert to clinical disease up to 3 mo after birth when maternal Abs begin to wane (11, 38, 39). Human studies have shown that during maternal malaria, levels of IL-10 are increased, whereas levels of TNF-α, TGF-β, and IFN-γ are lower in peripheral blood and in the placenta (40, 41). During early childhood, maternal malaria can impact offspring susceptibility to malaria, depending on the parasitemia of the mother. Specifically, if the parasitemia of the mother is low, there is an increased risk of the child developing malaria in infancy compared with heavily infected mothers (42, 43), highlighting the importance of the transfer of high levels of protective maternal Ab in newborns. Additionally, the transfer of both malaria-specific Abs and Abs induced by immunizations, such as tetanus, are reduced during placental malaria (44, 45).

Another congenital protozoan infection that is associated with low birth weight and preterm delivery is toxoplasmosis (46). Clinical manifestation ranges from fever and jaundice to microcephaly and increased risk of cognitive disabilities (46–48). In children with ocular lesions, which can occur up to 10 y after birth and in ∼24% of children born to mothers infected with Toxoplasma gondii (30, 49), there is an expansion of proinflammatory monocytes and NK T cells, along with an increase in activated B cells (50). Children with congenital toxoplasmosis have higher levels of TNF-α and IL-1 than acquired and asymptomatic individuals, along with lower production of IL-12, high levels of which are implicated in resistance to infection (51). During chronic toxoplasmosis, TNFs are a critical feature of the immune response, protecting the host from death (52), suggesting that congenitally infected individuals have a hyperresponsive reaction to infection with toxoplasmosis, leading to chronic disease.

Helminths are parasitic worms (53) that currently infect ∼1.5 billion people worldwide (54). Because of the size of adult helminths, of which the diameter ranges from 100 to 350 μm (55), they cannot pass the placental barrier, where the maximum size of entry is 250 nm (56). Although congenital infection does not usually occur, maternal helminth infection still causes low birth weight (57) and stillbirth (58) and is associated with reduced cognitive function at 1 y of age (59). Overall effects of maternal helminth infection on offspring immunity include increased levels of IgE, IL-8, IL-6, IL-10, and TNF-α (60, 61). The most common helminth infections are soil-transmitted intestinal helminths, such as ascaris and hookworm, mosquito-borne lymphatic filarial worms, and the water-transmitted trematode schistosomiasis (62), all of which have been shown to cause maternal infections that are thought to modulate the immunity of offspring.

Maternal lymphatic filariasis has been shown to lead to increased early childhood susceptibility to bancroftian filariasis, a phenomenon thought to be driven by transplacental transfer of filarial Ags such as circulating filarial Ag (63, 64). In utero filarial Ag transfer is associated with increased levels of cord blood IL-10 and decreased levels of IFN-γ (63) and the development of Ag-specific T cell responses that mirror that of patent adult infection (65). This increased production of cytokines persists into early childhood and in separate studies was associated with increased susceptibility to Wuchereria bancrofti infection (20), suggesting that this immunomodulation primed in utero has long-lived effects. One cellular mechanism that may underlie this long-term modulation is an increase in the development of regulatory T cells (Tregs). Indeed, recent work has found that there is a marked increase in Tregs producing IL-10 in both the cord blood and during early childhood (66).

In maternal ascariasis, increased plasma levels of IL-10 at birth are associated with increased susceptibility to subsequent ascaris infection by inducing a tolerizing effect (67). Increased levels of IgE, due to low-dose exposure to helminth Ag during maternal ascariasis, are linked to increased rates of allergy and allergic asthma (68, 69). Additionally, cord blood from ascaris infected mothers have higher frequencies of IFN-γ– and IL-4–expressing CD4⁺ T cells in response to ascaris Ag stimulation, indicating that this immunomodulation occurs in utero (15).

Similar to maternal filariasis, maternal schistosomiasis has been shown to sensitize neonatal T cells, inducing Ag-specific production of IL-5, IL-10, and IFN-γ (65). The most studied consequence of maternal schistosomiasis is decreased vaccine efficacy, which has been observed for the hepatitis B (70), bacillus Calmette-Guérin (71), and measles vaccines (18). Elevated levels of IL-10 in cord blood are a biomarker of decreased vaccine efficacy in maternal schistosomiasis (72). Although a specific mechanism has not been attributed to these changes, a recent study has found that there is a decrease in H4 acetylation at the IL-4 loci in murine pups born to schistosome-infected dams (73), implying that at least in the mouse model, there are long-lived epigenetic changes that can alter offspring immunity. It has also been shown that murine pups from chronically infected mothers have an impaired humoral immune response, including lower frequency and impaired proliferation of B cells linked to transcriptional changes in key cell cycle and B cell identity genes such as EBF1 and the JUN/JUNB pathways, leading to lower vaccine-induced humoral immunity (74). Taken together, these data suggest that similar to maternal filariasis, offspring immunomodulation induced by maternal schistosomiasis may last long into childhood, a possibility bolstered by recent work that demonstrated that anti-measles Abs remain suppressed at 2 y of age in children born to Schistosoma mansoni–infected mothers (18). It has also been shown that during a subsequent infection with schistosomiasis, murine pups born to infected mothers have increased tolerance to infection (5, 75). This has not been corroborated in humans, but it has been shown that there is schistosome-specific IgE and increased naive, low-affinity B cells in cord blood during maternal schistosomiasis (76), indicating sensitization of the B cell arm of the immune system to schistosomes. Although treatment during pregnancy has recently been approved (77), ∼26% of worms survive the recommended drug treatment course, suggesting that either that efficacy is lower than previously thought or there are drug-resistant isolates (78). Moreover, anthelminthic treatment for either soil-transmitted helminths or schistosomiasis during pregnancy does not appear to benefit offspring vaccine response or improve anemia (79) and leads to an increase in infantile eczema, one of the earliest-onset allergic diseases (80). Interestingly, this increase in allergic disease following maternal anthelminthic treatment has also been found with maternal treatment with albendazole in hookworm- and ascaris-infected mothers (81). This association with allergic disease has been mechanistically examined in a murine model in which maternal schistosomiasis protects from the development of allergic airway disease in an IFN-γ–dependent manner (82). These data suggest that some changes in immunity imprinted by maternal infection may be immunologically beneficial and that maternal anthelminthic treatment may not provide a clear benefit to offspring, so treatment policies need to be researched further.

Parasitic infection during pregnancy can be detrimental to both the mother and fetus. Maternal consequences of parasitic infection include anemia (83, 84), which can lead to low birth weight (85) and an increased risk of stillbirth (86). Interestingly, an increased risk of stillbirth has not been strongly associated with maternal parasitic infection in non-white populations (86–88). This leads to the conclusion that although maternal infection can cause maternal anemia that leads to low birth weight, it does not increase the risk of stillbirth in African cohorts and may be a consequence of maternal inflammation and infection, as seen in other maternal infection models (89–91). For the offspring, parasitic infections, both maternal and congenital, cause an increase in activation markers on immune cells in cord blood. Major cytokines and chemokines that are altered in maternal and congenital infection are IL-1, IL-4, IL-12, TNF-α, and IFN-γ. These changes are inconsistent among parasitic infections, similar to the diversity in the immune response to these parasites in nonpregnant individuals (Fig. 1). This suggests that because of the complexity of the immune response to parasitic infection, which can vary across the spectrum of Th1 to Th2 (92) depending on the stage of infection and severity of disease, the long-lived effects on the immune system of the offspring are likely to be varied and may not be detectable at birth.

As discussed, there seems to be an increase of steady-state cytokine levels of IL-6 and IL-10 in cord blood (Fig. 1), both of which are often secreted as an effort to restore homeostasis after inflammation (93), indicating that children born to parasite-infected mothers have altered inflammatory steady-state immunity at birth. IL-6 is important for embryo implantation and placental development with increased levels associated with miscarriage (94), suggesting a mechanistic role of this cytokine in fetal loss and growth restriction in infected women. More importantly, IL-6 has been shown to be elevated in other maternal inflammation models (95–97), whereas IL-10 has been shown to be decreased in neonates from women with maternal viral and bacterial infections and during homologous adult infection (98–101). This indicates that IL-6 may play a role in the maternal/fetal inflammation response that is independent of Ag, but that IL-10 in the cord blood, likely produced by the offspring, is dependent on the type of maternal infection/inflammation and is Ag-driven. Because of these cytokine changes, specifically in IL-6 and IL-10, it is unsurprising that these offspring often have increased susceptibility to multiple infections. IL-6 overexpression is known to be advantageous to viral and parasitic pathogens, often promoting their reproduction and survival. Meanwhile, IL-10 expression can lead to activation of Tregs, causing a broad suppression of the immune system. These coupled together create an opportunistic environment for pathogen survival in the context of maternal parasitic infection. Thus far, cord blood IL-10 is the most predictive biomarker of altered offspring immunity across maternal parasitic infections, but further studies are needed to validate this and identify additional biomarkers of offspring immunomodulation.

One critical facet of maternal infections is the transfer of maternal Abs to offspring. It has been shown that maternal IgG Abs can cross the placenta in an FcRn receptor–dependent manner (102). During parasitic infection, there is an increased transfer of IgE in addition to IgG. It has been shown that maternal IgE during allergy can transfer allergy sensitivity to offspring by mast cell activation (103), suggesting a possible mechanism of in utero sensitization during maternal infection, whereas helminth-infected mothers transfer IgGs and IgE, leading to decreased sensitization. Maternal Ab is also transferred during breastfeeding, which has been shown to give protection to infants against infection (104). Although there is little information about in utero Ab exposure versus breast milk exposure and the differential outcomes on offspring immunity, it is known that mainly Ag-specific IgGs are transported across the placenta and that IgA is the dominant class of Ab in breast milk and has been shown to be anti-inflammatory and promote the gut and microbiome of the infant (105). This is corroborated by a murine study looking at the effects of being born to a helminth-infected mother versus being suckled by one in which the suckled had protection against subsequent infection and the born had increased infection (106). Although there are two routes of Ab transfer, it has been shown that there is decreased Ab transfer during placental malaria (107), indicating that these infants do not have the same level of protection against many vaccine-preventable diseases as other infants, especially during the neonatal period in which protection from maternal Abs is essential. The role of other maternal parasitic infections on maternal vaccine–induced Abs needs further study.

The study of maternal parasitic infections is a rapidly expanding field. Although childhood mortality rates are decreasing, areas with endemic parasites still have the highest rates of childhood mortality. Because cure failure to antiparasitic treatment is increasing (108–110), there is a critical need to understand the consequences of maternal infection on the development offspring immunity. Because of their increased risk of altered immunity due to maternal inflammation and a decrease of passive Ab transfer, maternal parasitic infections and the mechanism behind their adverse immunomodulation must be uncovered to improve vaccine regimens and reduce childhood morbidity in endemic regions.

The authors have no financial conflicts of interest.

Institutional History

• Associate Professor, University of Utah, 2021–present

• Assistant Professor, University of Utah, 2018–2021

• Assistant Professor, Purdue University, 2014–2018

• Instructor, Washington University in St. Louis, 2014

• Postdoctoral Fellow, Washington University in St. Louis, 2012–2014

• Postdoctoral Fellow, Trudeau Institute, 2009–2011

• Ph.D., Yale University, 2004–2009

• B.A., University of Chicago, 1999–2003

Research Interests

• Schistosomiasis

• B cell development and memory

• T follicular helper cells and CD4 memory

• Macrophages

• Maternal infection/inflammation

• Immunometabolism

• Vaccine induced memory

• Hematopoiesis

I have known I wanted to be a scientist since I was a child experimenting with worms and bugs in the backyard. Jane Goodall was my childhood hero, and I thought I wanted to be either a primatologist or a paleontologist. I started doing research in high school in the High School Honors Science, Math, and Engineering Program at Michigan State University, working in toxicology and endocrinology labs over two summers. During that time, I read Michael Crichton’s The Andromeda Strain and fell in love with microbial pathogenesis, the research I have pursued since. In high school and college, I never saw professors who looked like me. This continued until the third year of my Ph.D. when I worked as a teaching assistant in the STARs summer program (a STEM training and mentoring program for women and minorities), in which I met the program coordinator Dr. Iona Black, a Black female faculty member in chemistry. It was then I realized how much I had needed to see someone that looked like me doing research and teaching at an elite institution. This experience solidified my commitment to become the role model I wish I had. Since that time, my commitment to fostering the true inclusion of underrepresented minorities and women in STEM has become equally as important to me as my research accomplishments. This commitment has also influenced my research interests. My scientific love for parasites is driven by their complex interactions and co-evolution with the mammalian immune system. But this interest is equally driven by the disparity between the devastating immunological and economic effects that parasites have on the majority of the world’s population and the resources spent on research and treatment of these diseases. Furthermore, a majority of my service efforts are directed towards fostering underrepresented minority trainees in tropical medicine through the American Society of Tropical Medicine and Hygiene, immunology, microbiology, and metabolism through programs I have developed at the University of Utah.

Keke Fairfax, Ph.D., Associate Professor

University of Utah, Salt Lake City, UT