Lights and Shadows of TORCH Infection Proteomics

Abstract

Congenital abnormalities cause serious fetal consequences. The term TORCH is used to designate the most common perinatal infections, where: (T) refers to toxoplasmosis, (O) means "others" and includes syphilis, varicella-zoster, parvovirus B19, zika virus (ZIKV), and malaria among others, (R) refers to rubella, (C) relates to cytomegalovirus infection, and (H) to herpes simplex virus infections. Among the main abnormalities identified in neonates exposed to congenital infections are central nervous system (CNS) damage, microcephaly, hearing loss, and ophthalmological impairment, all requiring regular follow-up to monitor its progression. Protein changes such as mutations, post-translational modifications, abundance, structure, and function may indicate a pathological condition before the onset of the first symptoms, allowing early diagnosis and understanding of a particular disease or infection. The term "proteomics" is defined as the science that studies the proteome, which consists of the total protein content of a cell, tissue or organism in a given space and time, including post-translational modifications (PTMs) and interactions between proteins. Currently, quantitative bottom-up proteomic strategies allow rapid and high throughput characterization of complex biological mixtures. Investigating proteome modulation during host-pathogen interaction helps in elucidating the mechanisms of infection and in predicting disease progression. This "molecular battle" between host and pathogen is a key to identify drug targets and diagnostic markers. Here, we conducted a survey on proteomic techniques applied to congenital diseases classified in the terminology "TORCH", including toxoplasmosis, ZIKV, malaria, syphilis, human immunodeficiency virus (HIV), herpes simplex virus (HSV) and human cytomegalovirus (HCVM). We have highlighted proteins and/or protein complexes actively involved in the infection. Most of the proteomic studies reported have been performed in cell line models, and the evaluation of tissues (brain, muscle, and placenta) and biofluids (plasma, serum and urine) in animal models is still underexplored. Moreover, there are a plethora of studies focusing on the pathogen or the host without considering the triad mother-fetus-pathogen as a dynamic and interconnected system.

Keywords: TORCH; congenital abnormalities; infections; mass spectrometry; pregnancy; proteomics.

Figure 1

Most frequent symptoms related to TORCH (toxoplasmosis, “others”, rubella, cytomegalovirus infection, and herpes simplex virus infections) diseases. Children can present these symptoms at birth or late, therefore medical follow-up is crucial (A). Main stages of bottom-up and top-down proteomic analysis. Different tissues, cell culture or fluids can be analyzed (B).

Figure 2

Main forms of maternal–fetal transmission of cytomegalovirus (A). Main findings indicated by proteomic studies that explore the proteome of human cytomegalovirus (HCVM) infection (B).

Figure 3

Main symptoms in children who contracted HIV through vertical transmission. Macrophages and microglia are reservoirs for viral multiplication and their immune functions are impaired (A). Main findings indicated by proteomic studies that explore the proteome of HIV infection (B).

Figure 4

Congenital HSV infection can affect multiple organs, the central nervous system (CNS) and eyes, mouth and skin of newborns. Medical treatment is essential to avoid severe and irreversible damage (A). Main findings indicated by proteomic studies that explore the proteome of HSV infection (B).

Figure 5

Malaria transmission cycle and representative proteomics-driven studies. (A) (1) Protozoa are transmitted to humans in the form of sporozoites through the bite of the female Anopheles mosquito. (2) Sporozoites reach the bloodstream and reach the liver, where they replicate in hepatocytes and mature in schizonts. Schizonts break and release merozoites. (3) Merozoites are capable of infecting erythrocytes, and initiate a cycle of asexual reproduction. Merozoites released in this step can restart a new cycle of asexual reproduction or they can start a cycle of sexual reproduction. (4) In sexual reproduction, male or female gametocytes are formed from merozoites. (5) Gametocytes can be absorbed by mosquitoes during the bite and start a cycle in the insect’s digestive tract. (6) Fertilization occurs that originates the oocyst, which migrates to the mosquito’s hemocele and releases sporozoites, which migrate to the mosquito’s salivary gland. Thus, when biting a new host, the cycle is restarted (1). (B) Main results of representative proteomic studies applied to malaria disease.

Figure 6

Toxoplasmosis transmission cycle and representative proteomics-driven studies. (A) (1) In the cat, after ingesting tissues containing oocysts or cysts, these are released into the body and penetrate the intestinal epithelium where they undergo asexual reproduction followed by sexual reproduction, transforming into oocysts and can be excreted together with the feces. Oocysts can survive for months in the environment and are resistant to disinfectants, freezing, and drying, but destroyed by heating at 70 °C for 10 min. Other animals, such as pigs, sheep, rats, and including man (2) (intermediate hosts), can consume oocysts present in the environment and become contaminated. The oocyst ruptures in the intestine of the intermediate host, releasing the sporozoites that invade the enterocytes. In the enterocyte, each parasite is called a tachyzoite. Tachyzoites spread through the animal’s body and can form cysts in nervous and muscular tissue, which can be consumed by humans and cause infection (3). Tachyzoite multiplies asexually and disrupts the host cell. After the invasion of a new cell by a tachyzoite, the asexual cycle can lead to the formation of intracellular bradyzoites. The formation of bradyzoites begins to occur with greater intensity when the intermediate host develops specific immunity. (B) Main findings indicated by proteomic studies that explore the proteome of toxoplasmosis infection.

Figure 7

In congenital syphilis, unlike infection in adults, Treponema pallidum is released into the fetus bloodstream and quickly reaches multiple organs. The main clinical symptom associated with disease in neonates is skin rashes, which spread throughout the body region. The main findings of the few studies that explore the proteome of syphilis infection are shown.