Unique challenges in the placenta

22 10 2012

Another cool article… found it on a blog by Dr. Venkat S. Karra, Ph.D. (M.Sc. Organic Chemistry; Ph.D. Chemical Sciences).  It focuses mainly on the placenta’s role in preventing illness in the fetus, but it does discuss initially the immunological dance between mother and embryo.

[Somehow, I find myself wanting to debate with these resistant REs out there who keep telling their patients that RI is bogus.  (I have yet to find out why this one nurse is talking about a nonexistent association of reproduction specialists– as best I can tell it doesn’t exist, anyway… if anyone here knows of something called the American Association of Reproductive Medicine please give me more information.  I have googled and googled and can’t find it!  And I don’t mean the American Society of Reproductive Medicine, either.)]

Anyway, here is Dr. Karra’s article:

“It is very fascinating to know and see the mechanism of  the entire pregnancy period and how especially the immune system of women, a Unique Defense and Tolerance System, trains itself in protecting the fetus in order to give an healthy gift to the world.

Fetus at 18 weeks after fertilization 3D Pregn...

Complete understanding of this process, which I believe many not be possible in its entirety, help us understand how a system works in all walks of our activities in every day life – taking from birth to death and every thing in between within our body as well as outside world. I strongly believe that the activities in the outside are simply the duplication of what is actually happening in those nine months period in the uterus of the mother. I may be wrong, but this subject is something that I am making an effort to understand and explore with a hope to prevent especially the chronic diseases passing through the placenta to the fetus and then to the new little one so that one day we will hopefully see a world free from all kinds of diseases and suffering.

I understand it is ‘too much’ to expect ‘that much’ but lets hope because we never know…thus keep working for the better and healthy world.

In this context I come across the following recent article – very interesting and encouraging and thus thought to ‘share with you all ‘ on this platform and in its entirety.

This article presents “the review on recent evidence for innate placental barriers to infection and how these can be breached by pathogens.”

 

Unique Challenges in the Placenta

Authors:

Varvara B. Zeldovich1,2, Anna I. Bakardjiev1,2*

1 Department of Pediatrics, University of California, San Francisco, San Francisco, California, United States of America, 2 Program in Microbial Pathogenesis and Host Defense, University of California, San Francisco, San Francisco, California, United States of America

What Are the Unique Challenges of Mammalian Gestation?

Mammalian gestation creates an immunological paradox wherein the body must balance tolerance of an allogeneic fetus with protection against invading pathogens. Pregnancy has long been considered a state of immune suppression that, while necessary for reproduction, increases a woman’s susceptibility to infection [1]. However, mothers bear the responsibility of the most important biological task: to carry and to nourish their offspring. It is therefore fitting that a more nuanced picture is emerging of a tightly regulated maternal immune system that balances awareness of the fetus with mechanisms to protect against pathogens and to sustain a healthy pregnancy [2]. Recent evidence indicates that innate placental defenses comprise one such mechanism. Subversion of these defenses by pathogens can lead to pregnancy complications such as preterm labor or vertical transmission with fetal morbidity or mortality [3]. The Danger Model posits that tissue damage rather than foreign antigens trigger inflammation [4]. This notion encompasses the paradox of mammalian pregnancy and suggests that infection-based loss of placental integrity may be the route to complications.

Here we review recent evidence for innate placental barriers to infection and how these can be breached by pathogens.

What Is the Function and Structure of the Placenta?

The placenta is a chimeric organ made of maternal and fetal cells and has two main functions: to nourish and to protect the fetus. Understanding the structure of the placenta is key to understanding its functions (Figure 1A–B). Specialized fetally derived cells called trophoblasts differentiate into several subpopulations that perform critical placental functions. In humans, invasive extravillous trophoblasts (EVT) anchor the placenta in the uterine implantation site (decidua) where they are juxtaposed to maternal immune cells. EVT also invade and restructure maternal arteries to facilitate blood flow to the fetus; specifically, maternal blood flows into the intervillous space, where it bathes fetally derived villous trees. The surface of these villi consists of a syncytium, a fused multinucleate trophoblast layer that mediates nutrient and gas exchange between maternal and fetal tissues. To facilitate such transport its surface is covered by branched microvilli (Figure 1C), whose total surface area reaches approximately 12 m2 by the end of human gestation. While facilitating transport from mother to fetus, the syncytium must also protect the offspring from blood-borne pathogens. Indeed, the syncytium is resistant to infection with multiple diverse microbes that are important human pathogens during pregnancy (e.g., cytomegalovirus [CMV] [5], the bacterium Listeria monocytogenes[6], and the protist Toxoplasma gondii [7]).

Figure 1. Structure and barriers of the human maternal-fetal interface.

 

thumbnail

(A) Structure of the human placenta. Maternal and fetal tissues are in tones of red and blue, respectively. Adapted from [6]. See text for detailed explanation. (B) Enlargement of boxed area in panel A showing points of direct contact between mother and fetus. EVT, extravillous trophoblasts; SYN, syncytium. Adapted from [6]. (C) Scanning electron micrograph of first trimester human placenta showing the syncytial surface with profuse branched microvilli (courtesy of Susan Fisher, UCSF). (D) False-colored transmission electron micrograph of primary human EVT. Listeria monocytogenes (green) is trapped in endolysosomes (orange). Adapted from [23]. Bar, 1 µm.

It is important to note that placental structure differs between mammalian species (reviewed in [8]), which influences the relevance of in vivo models for human disease. For example, there are a number of differences between the human and mouse placenta that limit the utility of the mouse as an experimental model. Nevertheless, pregnant mice are used because of the availability of tools to study the host immune response to infection. In addition, isolated murine placental cell types that recapitulate human phenotypes might prove useful in the study of host-pathogen interactions in the placenta.

How Does the Syncytium Protect the Fetus from Blood-Borne Pathogens?

In order to cause infection pathogens have to be able to (a) adhere, (b) invade, (c) replicate, and/or (d) avoid elimination. The barrier created by the syncytium against diverse pathogens suggests that its general cell biological properties may interfere with these steps of microbial colonization and growth.

In order to understand how the syncytium resists microbial colonization, it is useful to compare the syncytium to other epithelial surfaces that can be breached by pathogens. For example, gastrointestinal pathogens typically use receptors that are components of intercellular junctions to breach the polarized epithelium of the intestinal barrier [9]. The formation of a fused multinucleate syncytium that foregoes intercellular junctions may therefore have evolved as a defense mechanism.

This is illustrated by studies of the food-borne pathogen L. monocytogenes, which breaches the intestinal barrier via the interaction of the virulence determinant internalin A with the host cell receptor E-cadherin that is transiently exposed at the tips of intestinal villi [10][11]. E-cadherin is typically not expressed on the apical surface of any epithelia, and thus its paucity of expression on the blood-bathed surface of the syncytium [6][12] coupled with the lack of intercellular junctions makes adherence and internalization of L. monocytogenes via this route unlikely.

Entry of herpes simplex virus into the syncytium is similarly inefficient, largely due to the lack of its host cell receptors HveA, HveB, and HveC [13]. Of note, the lack of intercellular junctions may also prevent transmigration of maternal blood leukocytes into the fetus [14], a process that must be tightly controlled for the sake of tolerance.

In addition, the syncytium has been shown to be resistant to infection by cell-to-cell spread of L. monocytogenes from infected macrophages [6], and direct invasion by T. gondii [7]. Surface receptors have not yet been identified for these processes, and it is possible that additional mechanisms contribute to the resistance of this specialized epithelium. For example, the network of profuse branched microvilli (Figure 1C) might preclude adherence of microbes as well as infected leukocytes.

Other explanations must be sought for the apparent resistance of the syncytium to infection from the basal side. L. monocytogenesT. gondii, and CMV can all be found in cytotrophoblasts underlying uninfected syncytium [5][7]. The basal surface of the syncytium may be guarded against invasion by the dense cytoskeletal network that supports such a laterally vast multinucleate cell [9]. The apical to basal directionality of nutrient transport machineries [15] may also preclude endocytic uptake of pathogens on the basal side. Furthermore, host cell invasion efficiency by L. monocytogenes has recently been linked to abundance of fused mitochondria [16]. Thus, the unusually fragmented state of mitochondria in the syncytium [17] may explain low invasion rates.

Finally, syncytial production of reactive nitrogen species has been hypothesized to reduce invasion and intracellular growth of Trypanosoma cruzi [18] and may contribute to elimination of other pathogens as well.

Thus, the syncytium creates a formidable barrier to infection by virtue of multiple unique cell biological properties. Furthermore, its function as a protective layer against blood-borne microbes and transmigration of maternal leukocytes may be the reason why all hemochorial placentas have evolved a syncytium [8].

What Is the Role of Extravillous Trophoblasts in Placental Defenses?

The resistance of the syncytium to infection begs the question where microbes breach the maternal-fetal barrier. The other point of direct contact between maternal and fetal cells is formed by EVT invading deep into the uterine implantation site, which contains an abundance of maternal leukocytes[2]. Macrophage precursors from maternal blood are actively recruited to the implantation site in the pregnant mouse model [19]. Is it possible for pathogens to hitch a ride? Indeed, multiple observations point in this direction. First, all pathogens that are known to infect the placenta and/or fetus have intracellular life cycles (Table 1[20], and most are able to infect and survive in leukocytes. Second, multiple studies demonstrate that intrauterine infection in vivo with a variety of different pathogens, including L. monocytogenes [21] and T. gondii [22], begins in the implantation site. Third, we have recently shown that EVT are the preferred site of entry for L. monocytogenes and T. gondii in primary human placental organ cultures [6][7].

Table 1. Placental pathogens.

thumbnail

However, EVT also have strong innate defense mechanisms against intracellular pathogens. We observed that spread of L. moncytogenes beyond EVT into deeper layers of primary human placental organ cultures was hindered [6]. In addition, isolated primary human EVT entrap L. monocytogenes in lysosomal compartments where they are degraded (Figure 1D[23]. EVT appear to be restrictive for viral growth as well. Recent studies indicate that the majority of HIV-1 virions are trapped within endosomal compartments in trophoblasts, and that EVT inactivate HIV replication mechanisms [24],[25].

These experimental systems suggest that innate host defense mechanisms in EVT may hinder the normal life cycle of intracellular pathogens and prevent microbial growth and spread. It is possible that the invasive role of EVT and their active breakdown of extracellular matrix may require unique degradative and endolysosomal pathways that interfere with the life cycle of intracellular pathogens.

Moreover, placental production of antimicrobials like β-defensins, indoleamine 2,3-dioxygenase, cathelicidin, and reactive oxygen and nitrogen species has been established [26] and may be responsible for EVT resistance to pathogens.

How Can Infection Progress and Lead to Pregnancy Complications?

Despite the effectiveness of the placental barrier, infections can nevertheless progress to cause pregnancy complications such as spontaneous abortion and preterm labor. While the molecular mechanisms of preterm labor are still poorly understood, it is associated with placental inflammation that may be triggered by infection and/or loss of placental integrity [3].

What factors contribute to the occasional progression of placental and fetal infection?

The “Danger model” suggests that the maternal immune system reacts to the presence of danger signals [4] and provides a plausible explanation for the paradox of mammalian gestation. The syncytial and EVT barriers may be effective until a certain threshold of cellular damage is accrued.

One possibility to reach this threshold occurs when several insults such as co-infection with multiple pathogens challenge the defense mechanisms of the placenta. Consistent with this model are the findings that human preterm placentas are often colonized with multiple microbes [27]. Similarly, histopathological analyses reveal that CMV is more often found in human placentas with concurrent bacterial infections [28], and more recently it has been shown that viral infection and bacterial products synergize to trigger preterm labor in the pregnant mouse model [29]. Another example is placental infection with Plasmodium falciparum, the causative agent of malaria. Parasite-infected erythrocytes accumulate in the intervillous space [30], which may lead to damage of the syncytium[31], and increased rates of vertical transmission of HIV-1 [32].

In summary, the placenta has developed powerful defenses against infection consisting of multiple layers of unique cell biological barriers. These innate safeguards dovetail with the modulated immune system during pregnancy to balance the need for tolerance with protection against pathogens. Damage of the feto-placental unit beyond a certain threshold triggers the termination of pregnancy—a sensible defense for mother and species.

Acknowledgments

We are deeply grateful to Susan Fisher for the scanning electron micrograph of human placental syncytium.

References

  1. Medawar PB (1953) Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates. Symp Soc Exp Biol 320–338. FIND THIS ARTICLE ONLINE
  2. Mor G, Cardenas I, Abrahams V, Guller S (2011) Inflammation and pregnancy: the role of the immune system at the implantation site. Ann N Y Acad of Sci 1221: 80–87. FIND THIS ARTICLE ONLINE
  3. Romero R, Espinoza J, Goncalves LF, Kusanovic JP, Friel L, et al. (2007) The role of inflammation and infection in preterm birth. Semina Reprod Med 25: 21–39. FIND THIS ARTICLE ONLINE
  4. Matzinger P (2002) The danger model: a renewed sense of self. Science 296: 301–305. FIND THIS ARTICLE ONLINE
  5. Fisher S, Genbacev O, Maidji E, Pereira L (2000) Human cytomegalovirus infection of placental cytotrophoblasts in vitro and in utero: implications for transmission and pathogenesis. J Virol 74: 6808–6820. FIND THIS ARTICLE ONLINE
  6. Robbins JR, Skrzypczynska KM, Zeldovich VB, Kapidzic M, Bakardjiev AI (2010) Placental syncytiotrophoblast constitutes a major barrier to vertical transmission of Listeria monocytogenes. PLoS Pathog 6: e1000732 doi:10.1371/journal.ppat.1000732.
  7. Robbins JR, Zeldovich VB, Poukchanski A, Boothroyd JC, Bakardjiev AI (2012) Tissue barriers of the human placenta to infection with Toxoplasma gondii. Infect Immun 80: 418–428. FIND THIS ARTICLE ONLINE
  8. Leiser R, Kaufmann P (1994) Placental structure: in a comparative aspect. Exp Clin Endocrinol 102: 122–134. FIND THIS ARTICLE ONLINE
  9. Delorme-Axford E, Coyne CB (2011) The actin cytoskeleton as a barrier to virus infection of polarized epithelial cells. Viruses 3: 2462–2477. FIND THIS ARTICLE ONLINE
  10. Lecuit M, Vandormael-Pournin S, Lefort J, Huerre M, Gounon P, et al. (2001) A transgenic model for listeriosis: role of internalin in crossing the intestinal barrier. Science 292: 1722–1725. FIND THIS ARTICLE ONLINE
  11. Pentecost M, Otto G, Theriot JA, Amieva MR (2006) Listeria monocytogenes invades the epithelial junctions at sites of cell extrusion. PLoS Pathog 2: e3 doi:10.1371/journal.ppat.0020003.
  12. Lecuit M, Nelson DM, Smith SD, Khun H, Huerre M, et al. (2004) Targeting and crossing of the human maternofetal barrier by Listeria monocytogenes: role of internalin interaction with trophoblast E-cadherin. Proc Natl Acad Sci U S A 101: 6152–6157. FIND THIS ARTICLE ONLINE
  13. Koi H, Zhang J, Makrigiannakis A, Getsios S, MacCalman CD, et al. (2002) Syncytiotrophoblast is a barrier to maternal-fetal transmission of herpes simplex virus. Biol Reprod 67: 1572–1579. FIND THIS ARTICLE ONLINE
  14. Ley K, Laudanna C, Cybulsky MI, Nourshargh S (2007) Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol 7: 678–689. FIND THIS ARTICLE ONLINE
  15. Nelson WJ (2009) Remodeling epithelial cell organization: transitions between front-rear and apical-basal polarity. Cold Spring Harb Perspect Biol 1: a000513. FIND THIS ARTICLE ONLINE
  16. Stavru F, Bouillaud F, Sartori A, Ricquier D, Cossart P (2011) Listeria monocytogenes transiently alters mitochondrial dynamics during infection. Proc Natl Acad Sci U S A 108: 3612–3617. FIND THIS ARTICLE ONLINE
  17. Wasilewski M, Semenzato M, Rafelski SM, Robbins J, Bakardjiev AI, et al. (2012) Optic atrophy 1-dependent mitochondrial remodeling controls steroidogenesis in trophoblasts. Curr Biol 22: 1228–1234. FIND THIS ARTICLE ONLINE
  18. Diaz-Lujan C, Triquell MF, Schijman A, Paglini P, Fretes RE (2012) Differential susceptibility of isolated human trophoblasts to infection by Trypanosoma cruzi. Placenta 33: 264–270. FIND THIS ARTICLE ONLINE
  19. Tagliani E, Shi C, Nancy P, Tay CS, Pamer EG, et al. (2011) Coordinate regulation of tissue macrophage and dendritic cell population dynamics by CSF-1. J Exp Med 208: 1901–1916. FIND THIS ARTICLE ONLINE
  20. Robbins JR, Bakardjiev AI (2012) Pathogens and the placental fortress. Curr Opin Microbiol 15: 36–43. FIND THIS ARTICLE ONLINE
  21. Redline RW, Lu CY (1987) Role of local immunosuppression in murine fetoplacental listeriosis. J Clin Invest 79: 1234–1241. FIND THIS ARTICLE ONLINE
  22. Ferro EA, Silva DA, Bevilacqua E, Mineo JR (2002) Effect of Toxoplasma gondii infection kinetics on trophoblast cell population in Calomys callosus, a model of congenital toxoplasmosis. Infect Immun 70: 7089–7094. FIND THIS ARTICLE ONLINE
  23. Zeldovich VB, Robbins JR, Kapidzic M, Lauer P, Bakardjiev AI (2011) Invasive extravillous trophoblasts restrict intracellular growth and spread of Listeria monocytogenes. PLoS Pathog 7: e1002005 doi:10.1371/journal.ppat.1002005.
  24. Ross AL, Cannou C, Barre-Sinoussi F, Menu E (2009) Proteasome-independent degradation of HIV-1 in naturally non-permissive human placental trophoblast cells. Retrovirology 6: 46. FIND THIS ARTICLE ONLINE
  25. Vidricaire G, Tremblay MJ (2005) Rab5 and Rab7, but not ARF6, govern the early events of HIV-1 infection in polarized human placental cells. J Immunol 175: 6517–6530. FIND THIS ARTICLE ONLINE
  26. King AE, Paltoo A, Kelly RW, Sallenave JM, Bocking AD, et al. (2007) Expression of natural antimicrobials by human placenta and fetal membranes. Placenta 28: 161–169. FIND THIS ARTICLE ONLINE
  27. Onderdonk AB, Hecht JL, McElrath TF, Delaney ML, Allred EN, et al. (2008) Colonization of second-trimester placenta parenchyma. Am Journal Obstet Gynecol 199: 52 e51–52.e10. FIND THIS ARTICLE ONLINE
  28. Pereira L, Maidji E, McDonagh S, Genbacev O, Fisher S (2003) Human cytomegalovirus transmission from the uterus to the placenta correlates with the presence of pathogenic bacteria and maternal immunity. J Virol 77: 13301–13314. FIND THIS ARTICLE ONLINE
  29. Cardenas I, Means RE, Aldo P, Koga K, Lang SM, et al. (2010) Viral infection of the placenta leads to fetal inflammation and sensitization to bacterial products predisposing to preterm labor. J Immunol 185: 1248–1257. FIND THIS ARTICLE ONLINE
  30. Fried M, Duffy PE (1996) Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta. Science 272: 1502–1504. FIND THIS ARTICLE ONLINE
  31. Crocker IP, Tanner OM, Myers JE, Bulmer JN, Walraven G, et al. (2004) Syncytiotrophoblast degradation and the pathophysiology of the malaria-infected placenta. Placenta 25: 273–282.FIND THIS ARTICLE ONLINE
  32. Bulterys PL, Chao A, Dalai SC, Zink MC, Dushimimana A, et al. (2011) Placental malaria and mother-to-child transmission of human immunodeficiency virus-1 in rural Rwanda. Am J Trop Med Hyg 85: 202–206. FIND THIS ARTICLE ONLINE

 

 

Advertisements

Actions

Information

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s




ourlastembryo's Blog

Endometriosis & Infertility. The road to overcoming invisible illnesses

The Jiu-Jitsu Vortex

Brazilian Jiu-Jitsu: More Gravitational Pull than a Black Hole

Everyday Mom Style

Fashion and Style Advice for Everyday Moms

WishfulBabybump

My IF Journey to MOTHERHOOD!

ReproRenegade

one woman's quest to repossess her fertility

Conceivable Solutions

Reproductive Immunology and Infertility Consultant

Bring on the Babies...

Adventures in Infertility and Reproductive Immunology

conceptionchronicles

Read my journey through infertility over the last 8 years...

2 Lovebirds + 1 More, Please?

All About IVF with PGS and Reproductive Immunology

My Preconceived Life

trying to add another person to the planet

The Joy Of an Embryo-Sitter

Adventures in Infertility and Reproductive Immunology

Hyperbole and a Half

Adventures in Infertility and Reproductive Immunology

Two Good Eggs

Two cracked eggs find the sunnyside (and funny side) of trying to conceive

INFERTILIT-HE

Adventures in Infertility and Reproductive Immunology

hopefulandhungry

The road to conceiving a baby....enjoying food and life along the way

Scrambled Eggs

using science to make a baby

Journey To the Finish Line

PR's, toddlers, hopes and dreams; I'm always running after something

The Knocked-Up Hopeful

Trials In Getting Knocked-Up

Kit and Kabooble

A travelogue through the world of breast cancer

Baby Steps to Balance

Finding a healthy balance on the road to baby

Idiotic Infertility

My Diminished Ovaries and Me

These Rotten Eggs

An Infertility Journey

Immotileturtle's Blog

Just another infertile rocking in a fertile world

Why Can't We Do This The Easy Way?

Our journey through the boggy waters of surrogacy

Thought Provoking Moments

He & Me Plus 3: Life With Triplets Un-wrapped

ladyblogalot.com

Okay, so, it’s not like I think everything I say and do is so damn awesome that everyone should know about it. In a blog. It’s just that as if being blind, and a vegetarian, with anxiety/OCD, and having the ability to accidentally break almost anything, and not liking chocolate, would be enough. But no. I also have to have IVF. Could I be any more minority? So it’s like god is playing one big joke on me… and I am not going down without a fight. In fact, God, I’m going to tell your mum on you. Well I would if my knowledge of religion was good enough for me to figure out who your mum is. Eve? Is it Eve? Well, Eve, this is what your son has been up to, and God, I just got you grounded pretty much forever. In your face, God. Ha.

The Quest to be a Mom

Adventures in Infertility and Reproductive Immunology

%d bloggers like this: