Exposure to infections during the first part of fetal life, the so-called teratogenic window, can cause severe brain malformations. To the established human neuroteratogenic pathogens (Toxoplasma gondii, Other pathogens, Rubella, Cytomegalovirus, and Herpes simplex virus; TORCH), Zika virus (ZIKV) is now added (1–3). Perinatal, infant, and childhood infections may also disturb the developing nervous system during the peaks of neurocircuit formations and possibly cause more subtle changes in brain maturation. Thus, cognitive impairments and behavioral disturbances in children born to HIV-infected mothers (4) or subjected to childhood malaria (5) have been described in SSA; unprovoked late-onset epilepsy may also occur following the latter infection (6).

Of particular concern to African neuroscience are emerging viral infections. They can reveal associations between infections and rare sequelae in human populations, as poliomyelitis once did for “infantile paralysis” (7). Early life viral infections may, in one way or the other, be implied in the pathogenesis of cognitive and neuropsychiatric disturbances: the “neurodevelopmental hypothesis” for late-onset brain dysfunctions [e.g., Ref. (8)]. By comparing four neuroinvasive infections originating from sub-Saharan Africa (SSA), i.e., ZIKV, West Nile virus (WNV), Chikungunya virus (CHIKV), and Ebola virus (EBOV), we find that they attack the human brain at various stages of development. Thus, time windows for viral invasions, given by occurrence of the emerging epidemics, may reveal unique associations between viral infections and late-onset human brain disturbances.

The emerging viruses dealt with in this review are indigenous to and were first identified in Africa (Figure 1). WNV was isolated from a woman, who had a mild febrile illness in the West Nile Region of Uganda in 1937 (9). ZIKV was first isolated from a Rhesus monkey, placed on a platform as bait for mosquitoes in studies on yellow fever in the Zika forest, in Uganda in 1947 (10). CHIKV was first isolated in 1953 at the Uganda Virus Research Institute from samples collected in Tanganyika (11). In 1976, the investigation of concurrent outbreaks of a hemorrhagic fever syndrome in Zaire (currently Democratic Republic of Congo) and Sudan (currently Republic of South Sudan) led to isolation of two viruses now referred to as EBOV and Sudan virus, respectively. Another member of the EBOV, Bundibugyo Virus was identified in Uganda (12) (Figure 1).

All these viruses, which are endemic in tropical SSA, have had outbreaks also in other African regions, e.g., WNV in north and west Africa, in South Africa, and in Madagascar during the last decade (13). Currently, there is an outbreak of CHIKV in Kenya. The mosquito-borne WNV, ZIKV, and CHIKV have spread worldwide out of Africa. For instance, WNV is the most common cause of encephalitis in the US, enhanced by the bird reservoir hosts (14). CHIKV has caused extensive epidemics on islands in the Indian Ocean, in particular, La Reunion (15–17). The spread of these emerging viruses into previously unaffected regions can be attributed to more frequent and distant travels, evolution of mutant viral strains with altered virulence, and changes in climate and local ecosystems.

Neuroscientific research is important to design specific, repellant molecules that reduce mosquito’s attraction to humans. Three of the emerging infections discussed are mosquito-borne, i.e., Aedes aegypti for CHIKV and ZIKV and Culex pipiens for WNV; Aedes albopictus can also host ZIKV (18). Neurophysiological and behavioral studies have revealed A. aegypti attraction cues emanating from humans [e.g., Ref. (19)]. Odor is one important cue of insect host-seeking behavior [e.g., Ref. (20)]. The mosquito’s olfactory receptor neurons can detect various odor volatiles from the human host, which make some people more attractive than others to mosquitoes. Carbon dioxide (21), lactic acid (22), and visual cues (23, 24) can also attract mosquitoes to the host. Neuroanatomical studies have uncovered the organizations of olfactory centers in the mosquito brain (25), and multimodal integration of carbon dioxide, body odor, and temperature cues in the mosquito brain can enhance mosquito attraction to humans (26). Novel strategies that specifically block more than one sensory cue for attraction of insects are envisioned to contribute to control of emerging viral spread and outbreaks.

Following the sting of an infected insect, neurotropic viruses enter through the skin, replicate in susceptible cells, and spread to the central nervous system (CNS) via peripheral nerve fibers and/or the bloodstream (27). WNV can directly spread by the former route (28), while viral spread via the bloodstream into the brain is hampered by barriers, i.e., the blood–CSF barrier and the blood–brain barrier (BBB), established early during embryonic life (29). Nevertheless, certain viruses pass across these barriers and target neural cells. Of the presently described viruses, the BBB may be crossed by WNV (14), ZIKV (see below), and probably also EBOV (30), while CHIKV can pass the blood–CSF barriers through the permeable choroid plexus to infect ependymal cells in a mouse model (31).

During pregnancy, viruses can enter the fetal brain through the bloodstream following placental transmission. Importantly, the placental structure as well as its expression of receptors used by various viruses and its innate immune response differ markedly between humans, mice, and ruminants, which hinders direct comparisons among animal species (3). Notably, human fetal immune adaptations provide early postnatal protection against extracellular pathogens but enhance the risk of virus-induced persistent infections (32).

The effects of an intrauterine infection depend on timing of the insult with highest vulnerability during peaks in neuronal cell proliferation and migration (33). In humans, simplified gyral patterns may result from disturbed cell migration at 8–16 weeks of gestation. While congenital microcephaly (reduced head circumference) is associated with various insults causing disturbed proliferation, migration, or destruction of cells at various periods of intrauterine life (34). Since the human brain increases about 3.5 times in weight after birth, when neuronal network formation and myelination are at their peaks, the question can be posed whether infant/childhood infections may cause less conspicuous, functional disturbances of the developing nervous system than malformations as long-term or late-onset effects [Figure 2A; (29)]. In fact, a register-based study has indicated that children with severe viral CNS infections at 0.5–8 years of age show enhanced risk of psychotic illness when they reach young adulthood (35).

Spurred by the great awareness of ZIKV-induced microcephaly, data on molecular mechanisms underlying this teratogenic virus infection are now rapidly accumulating. Here, we briefly review some recent findings and indicate gaps-in-knowledge for neuroscience to fill not only for teratogenesis but also for potential postnatal developmental disturbances in this and the other emerging viral infections.

Nowakowski et al. (66) suggested that AXL could be a candidate as a receptor for endocytotic entry of ZIKV into the fetal brain. AXL is a member of the multifunctional TAM receptor protein tyrosine kinase family that among other things regulates phagocytosis and plays a pivotal role in innate immune responses (67). In the human fetal brain, AXL is expressed in neural stem cells that generate neurons populating the neocortex, radial glial cells, astrocytes, and endothelial cells [Figure 2B; (66)]. From an infected mother, ZIKV may have a privileged entry to the placenta as indicated by the finding that it infects human endothelial cells of the umbilical vein in culture by binding to AXL with a high efficiency compared to other flaviviruses, such as WNV (68). Additional evidence suggests that the ZIKV infects other cells of the placenta, e.g., macrophages and cytotrophoblasts (69). Chavali et al. (70) recently demonstrated that the ZIKV has a predilection in its RNA genome to bind to a specific RNA-binding protein (Musashi-1), which is liberally expressed in the radial glial cells. Since these progenitor cells are precursors for neurons and astrocytes that form the cerebral cortex (71), this binding capacity may directly influence formation of the cerebral cortex.

Additional experiments using various types of cell culture have been useful in furthering our knowledge of ZIKV infection, especially on neural progenitor cells. Direct infection of human tissue placed in culture shows special susceptibility of radial glial and epithelial stem cells, while demonstrating limited direct infection of neurons (72). Since human progenitor cells form three-dimensional organoids in culture, they demonstrate features of radial glial cells, which also show evidence of specific direct infection in culture in this model. Numerous other experiments using various cell culture models and direct infection of vertebrates also demonstrate involvement of radial glial-like cells and progenitor cells [for review, see Ref. (73)]. This apparent focus of infection specificity to neural progenitor cells may help to clarify the preferential effect of ZIKV on the fetus leading to microcephaly.

Development of animal models is clearly an essential route to more completely understand ZIKV effects on the brain and the nervous system. Several such models exist to study effects of ZIKV infections in offspring to pregnant animals, but none of them fully replicate the human situation [for review, see Ref. (74)]. Viruses mostly need adaptations to a new animal species, the neurovirulence between viral strains differs, the placental immune response and receptors that viruses use differ between species (see, above), and even within the same species, such as mice, various strains differ markedly between their reactions to an infection. Nonetheless, offspring to ZIKV-infected immune-deficient mice and non-human primates have shown some abnormalities in the brains (74). Considerable efforts are needed for neuroscience–microbiology collaborations to develop suitable animal models of viral infections to disclose and validate not only neuroteratogenic viral effects but also more subtle alterations that may result from prenatal abortive or persistent infections.

We present evidence that various spectra of neurodevelopmental disturbances may be associated with the emerging viral infections: ZIKV with congenital microcephaly following intrauterine infections, but also postnatal brain alterations with or without microcephaly; CHIKV with postnatal microcephaly following perinatal infections, but also behavior and communication disturbances; WNV with cognitive dysfunctions following infections mostly in adults, but infant/childhood infections are underestimated and need further studies. EVD, which has flared up in waves in SSA, may also be a threat to the developing human nervous system. Important gaps in knowledge include risks of cognitive impairment, behavior disturbances, and neuropsychiatric diseases following infections during infancy and childhood with these emerging infections, when neuronal network formation and synaptogenesis are at the peak. The molecular mechanisms resulting in disrupted neural development need to be unraveled in more detail and the possibility addressed whether some of these emerging viruses can persist in the human brain.

Based on this situation, we foresee a number of activities to reduce the menace of these infections to nervous system maturation:

Strengthening capacity of African virology and neuroscience research with enhanced worldwide collaboration to strongly benefit the community.

The authors contributed expertise information and presented one section each at a symposium with the same title at the SONA conference in Entebbe, Uganda, June 11–14, 2017. All the authors approved the final version of the manuscript.

The authors declare that the writing of this article was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.