Your name: Subigya Ranapaili

Academic year: 2023-24

Title: Mother to child transmission of Toxoplasma gondii

varies with the
trimester during which maternal infection was
acquired. Does the maternal
placenta and/or immune system play a role?

Word Count: 1939

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Mother to child transmission of Toxoplasma
gondii varies with the trimester during
which maternal infection was acquired.
Does the maternal placenta and/or immune
system play a role?

Introduction

Toxoplasma gondii, which is an obligate

intracellular protozoan, presents a
notable threat to human health globally
[1]. As shown in figure 1 [2], the
presence of toxoplasma gondii is
worldwide, thus research into this
infection is paramount. Furthermore as
shown on the map there are numerous
countries shaded white, this equals an
absence of data, this portrays whilst
toxoplasma gondii is a dangerous Figure 1 Global status of Toxoplasma gondii
seroprevalence. Dark red equals prevalence
infection it is not researched well above 60%, light red equals 40–60%, yellow
enough. 20–40%, blue 10–20% and green equals
prevalence <10%.

Although the infection is usually asymptomatic in individuals with a

healthy and normal immune system, it can lead to severe complications in
immunocompromised individuals and foetuses exposed during pregnancy
[3]. This intracellular parasite has a complex life cycle, involving many
hosts. The primary hosts are felids whereas intermediary hosts are those
such as mammals and birds [4]. Human infection can commonly occur
when ingesting oocysts shed in the faeces of infected cats or by
consuming undercooked meat containing tissue cysts. However, the
vertical transmission from mother to foetus during pregancy is a critical
route of infection which leads to congenital toxoplasmosis and is the
primary focus of this
paper.
 Figure 2 Life Cycle of T. gondii showing the three
infectious stages of T.gondii: tachyzoites, bradyzoites (in
The variation intissue
mother
cysts)to
andchild transmission
sporozoites (in oocysts)based on the
trimester of
[4]
maternal infection acquisition is an area of significant interest and clinical
importance. Since understanding the factors influencing this variation
could provide insights into the pathogenesis of congenital toxoplasmosis
and thus could lead to strategies for its prevention and management. In
this study, we aim to investigate the specific role of the maternal placenta
and immune system in modulating the transmission of toxoplasma gondii
during pregnancy.

Main Body
Trimester specific transmission rate
Multiple studies have repeatedly shown a significant and notable
correlation between the timing of maternal infection with Toxoplasma
gondii (T.gondii) during pregnancy and the likelihood of vertical
transmission to the foetus. Most studies come to the same conclusion that
infection of T gondii will pose minimal to zero risk to the foetus if the
mother contracts it prior to pregnancy, except in cases where women are
infected within three months before conception [5]. However, infection
during pregnancy is when the risk of foetal transmission becomes much
higher.

A study done by D Dunn et al shows us

that the risk of congenital infection
was minimal in foetuses of women
infected during early pregnancy with
only 6% at 13 weeks gestation (see
figure 3). Subsequently, as the
pregnancy progresses, the risk rose
sharply and consistently, reaching 40%
at 26 weeks and 72% at 36 weeks
gestation. Thus, this data shows that
while infection in early pregnancy
suggests small risk of transmission,
Figure 3 Risk of congenital infection by maternal infection in the third
duration of gestation at maternal
seroconversion. [6]
trimester often results in
asymptomatic newborns.
Another study done by Wallon et al [7] also examined the risk of
congenital infection with Toxoplasma gondii across different gestational
ages. Both studies reported similar findings about there being a minimal
risk of congenital infection when the maternal infection was developed in
early pregnancy. However, despite the congruence in results differences
in duration and sample sizes are notable. In the Wallon study a total of
2361 pregnant woman were diagnosed between April 1987 and December
2008 (see figure 4) [7] whereas in the Dunn study only 603 women were
analysed between 1987 and 1995[6]. Despite the disparity in sample sizes
between the studies, both sets of results revealed consistent findings. This
alignment suggests that the relationship between gestational age and risk
of congenital infection with toxoplasma gondii is a robust and reliable
association that holds across different sample sizes and study contexts.
Furthermore, in Wallon’s study he states that he included an “extended
recruitment period” and used a “homogenous selection criteria” yet the
results were extremely similar to Dunn’s study further showing that the
observed pattern is a genuine reflection of the biological processes
involved in Toxoplasma gondii transmission during pregnancy, which we
are going to investigate subsequently.

Figure 4 Probability of foetal infection according to

gestational age at the time of maternal infection
before and after mid-1992, Lyon cohort [7]

Role of maternal placenta

As we observed in the previous section, congenital toxoplasmosis is more

frequent when infection occurs during the third trimester. One possible
reason for this is due to the fact that during the third trimester placental
layers that are separating maternal blood from foetal blood become
thinner and blood flow then increases considerably [8]. However, in Faral-
Tello’s research [9] they specifically state that “How T. gondii crosses the
placental barrier, infects the trophoblast, reaches fetal vascularity and
disseminates, remains virtually unknown.” However, in this paper we will
attempt to propose a few different ideas on T gondii achieves this feat.

The placenta itself, is a temporary fetal-maternal organ. It is not only a

barrier, but it is also a tissue that interacts with the immune system. The
placenta is composed of many cell types, including trophoblasts, foetal
endothelial cells, and immune cells al of which aid it in its protective
functions. Trophoblasts form the outer layer of the placenta and play a
pivotal role in immune modulation and barrier function. These
trophoblasts form early after fertilisation but then can give rise to
cytotrophoblasts and synctiotrophoblasts [10]

Figure 5 Schematic representation of a human placenta at

two developmental time points. (A) Early placenta.(B) Term
placenta. Parasite structures indicating sites susceptible to T.
gondii infection are shown in green [9]
As shown in figure 5 [9]
the placenta is a developing organ, thus we can identify two scenarios
that represent periods of susceptibility for vertical transmission. One such
instance is when the foetal trophoblast is invading the maternal decidua
and so encountering spiral arteries during the first trimester. When this
occurs, parasites that are in the mother’s blood may directly contact
foetal cells. Another such scenario is during the second/third trimester the
barriers between foetal and maternal blood begin to diminish. [11]

Figure 6 Placental defences against pathogens. [12]

As previously stated, the placenta also has interactions with the immune
system as shown in figure 6. In the case of toxoplasma gondii, the
placenta releases numerous immunomodulatory factors such as
regulatory chemokines (CCl22) and CC17 in response to infection [13].
However, the exact impact of this signalling has yet to be determined.
Therefore, the overall general defence is usually the decidual layers that
contain numerous immune cells such as, cytotoxic, helper and regulatory
T cells, innate lymphoid cells, macrophages and neutrophils. Nevertheless,
even with all these defensive cells, one way Toxoplasma gondii could
infect the foetus is infecting and hiding in the maternal decidua, “trojan
horse” strategy thus evading all the host defences.

Role of maternal immune system

Following on from the placenta the maternal immune system also has
roles that impact the transmission of toxoplasma gondii. First of all, I shall
explain the two (adaptive and innate) responses we have towards
toxoplasma gondii then go specifically into the maternal side.

The most important part of the innate immune response to Toxoplasma

gondii is the body’s ability to sense the pathogen and then produce the
cytokine IL-12 [14]. This cytokine then goes on to stimulate natural killer
cells and T cells to produce IFN- γ [15] This interferon is a major factor in
the resistance of T. gondii and also promotes multiple intracellular
mechanisms to kill and inhibit toxoplasma gondii. [16]

Figure 7 Innate Immune response to Toxoplasma gondii [18]

The adaptive immune response to Toxoplasma gondii is paramount to a

successful long-term resistance. The CD4 T cells and CD8 T cells play
primary roles in controlling the infection [17].The CD4+ cells orchestrate
the initial response, via enabling the production of the potent cytokine
interferon gamma, which we first met in innate immunity, which rallies
immune cells to combat the parasite. The CD8+ T cells take a direct role
to eliminate infected cells and control chronic infection. However, factors
like checkpoint inhibitor therapies can compromise the functioning of the
CD8+ T cells.

Figure 8 Adaptive Immune response to Toxoplasma gondii [18]

A study done by Gomez-Chavez et al helps us understand the complex

relationship between maternal immunity and congenital transmission.
This study [19] explored the immune response of pregnant women
infected with toxoplasma gondii and its link to transmitting the parasite to
their newborns. Researchers analysed two key aspects which were
antibody levels (they looked at specific antibody subclasses in serum) and
the cellular response (measured the peripheral blood mononuclear cell
proliferation and cytokine production). The surprising finding was that the
women who transmitted the parasite had higher levels of certain
antibodies and increased lymphocyte proliferation. This challenges the
traditional view that was held, of maternal antibodies protecting against
transmission. Furthermore, the study highlighted the importance of T-cell
immunity. A key find was that an increased production of IFN-gamma was
observed in transmitting mothers. This suggests a potential link between
a strong immune response and transmission. Also, low levels of TGF-B
could contribute to transmission by allowing the parasite to spread,

Interplay between Placenta and Immune System

While the battle against toxoplasma gondii infection during pregnancy is

shown to have been fought on two fronts – the maternal immune system
and the placenta – surprisingly, direct research investigating the
combined influence of these factors on foetal infection risk remains
relatively quite scarce. This lack of comprehensive understanding
presents a significant gap in our knowledge. Thus, this section is mainly
going to my own understanding of the interplay and interaction between
these systems and some hypotheses I believe warrant further
investigation.

The first hypothesis I present is about how the gestational stage could
influence the combined effect of placental function and maternal immune
response on Toxoplasma gondii transmission. As we have seen earlier,
vertical transmission is more likely to occur in the third trimester rather
than the first. This could be because early pregnancy is characterised by a
more robust production of interferon gamma. Additionally, the placenta is
less developed in this stage, with tighter junctions between trophoblast
cells. This could act as a more formidable barrier against pathogen
passage. I hypothesise that this combination, a strong immune response
coupled with a less developed but tighter placenta, could create a more
effective barrier against toxoplasma gondii, potentially explaining the
lower transmission rates observed in the first trimester. Conversely, in the
third trimester the placenta becomes more permeable and the immune
system more modulated, which could create a window of vulnerability for
foetal infection, thus explaining the higher transmission rates observed in
this trimester.

The other hypothesis is one that suggests disruptions in placental

function, such as inflammation, can compromise the maternal foetal
barrier. I hypothesise that disruptions such as these could create an
increased rate of foetal toxoplasma gondii exposure. This could be due to
the compromised barrier allowing for increased parasite passage.
Secondly, the inflammatory environment could further modulate the
maternal immune response, which could lead to a decreased ability to
control the parasite’s proliferation, increasing the risk of foetal exposure.
However, further research is needed to explore the specific mechanisms
by which placental dysfunction influences the maternal immune response
and how this effects Toxoplasma gondii transmission.

Conclusion
Through this paper we’ve explored the concepts of how the placenta and
immune system influence the trimester specific transmission of
toxoplasma gondii. This holds great clinical significance as it can lead to
better judgement on how to handle congenital toxoplasma gondii. For
example, in Wallon’s [7] discussion they clearly state that maternal
toxoplasma infection should never automatically lead to termination.
Furthermore, we could use our knowledge about the intricate
choreography between placental function, and the maternal immune
response to suggest avenues for targeted interventions. Therapies that
safely help the mother and child could be explored.

However, our current knowledge remains incomplete. While existing

research provides a solid framework, we must proceed with further
studies to validate the hypotheses presented earlier and pinpoint specific
mechanisms at play. Investigating cytokine profiles and Immune cell
activity in mothers with varying gestational ages is paramount. By
prioritizing research efforts in this area, we can transform our
understanding of congenital toxoplasmosis and pave the way for the
development of effective preventive and therapeutic strategies.
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