The Role of Infectious Diseases in Mental Health

By Jeremy Aguinaldo
October 8, 2015

The pMR Neuroborreliosisurpose of writing this article is to highlight the role of infectious diseases in mental health. After infection from certain microorganisms, the symptoms they elicit can be straight forward. For example, after infection from the Rhinovirus (the Common Cold), it is expected to come down with runny nose, cough, sore throat, watery eyes, sneezing and fever. When an unvaccinated child is exposed to Chicken pox, that child is at risk to come down with itchy, red rash and blisters around the body. These pathogens follow a step-wise process that results in disease. After entry, these pathogens can damage the host through invading and multiplying within the tissues, produce harmful toxins, an indirect attack from the host own immune response, or a combination of all three and other possibilities. By knowing the mechanisms on how they harm the body, treatments can be tailored for each of these pathogens as well as for each person.

Ant fungus2Snail worms2The idea of small microorganisms influencing behavior seems like something from a science fiction/horror film. There are few examples in nature of pathogens altering the behavior of small insects and other creatures. The fungal species Ophiocordyceps infects ants, then take over its brain, and controls it to travel to an ideal location to infect other ants when its spores burst out of its body. A parasitic worm called Leucochloridium invades the eyestalks of snails, and pulsates in a manner that resembles a caterpillar. This would then lure hungry birds to ingest the infected snail, which is required for the parasite’s life cycle, which will release the eggs in the bird’s feces.

But what about humans? Can their behavior get modified from these simple creatures? Dracunculus medinensis (guinea worm disease) is found in parts of Africa, Middle East, and Asia. Humans become infected by drinking water contaminated with copepods which is harboring the larvae of the parasite. The larvae continues to mature and grow in the human and females usually migrate towards the skin surface, usually resulting in a blister or lesion. This has been described as incredibly uncomfortable with a burning sensation, with the only relief found in contact with water. Once contact has been made, the blister ruptures and the female worm release its larvae, and the cycle repeats. In order to complete its life cycle, the parasite modified the host’s behavior in wanting relief from such pain, and utilized that to its advantage.

Dracunculus extractionThese examples are very straight forward in terms of their mechanisms and what role they play. Efforts have been made in controlling guinea infection: drinking filtered water, control the copepods population, and even treating patients infected with the parasite directly. With the life cycle continually disrupted, it has been successfully eliminated in certain parts of the world. But there are some microorganisms that are not as straight forward as these examples. Their effects are more insidious. We would not know if we are even infected. And if we are, are the choices we make our own, or by the creature within?

Mental health is difficult in that it deals heavily on behavioral, biological, and societal influences. Sometimes, a simple oral tablet is not enough in recovery. I have researched a variety of infectious diseases and particularly which mental illnesses or disorders they are associated with. I found associations with schizophrenia and bipolar with endogenous retroviruses, autism from bacterial infections, intellectual disabilities from TORCH diseases (Toxoplasmosis, others like syphilis and HIV, Rubella, Cytomegalovirus, and Herpes Simplex). Delirium from Creutzfeldt-Jakob prions. Obsessive Compulsive Disorders (PANDAS) from streptococcal infection. Herpes Simplex I virus can be associated with multiple conditions such as schizophrenia, depression, and dementia.

I decided to focus on three conditions in particular: psychosis, mania, and depression. These features overlap with other mental illnesses such as Schizophrenia, Schizoaffective, Bipolar I and II, and Major Depressive Disorders. In addition, I also included Lyme Neuroborreliosis caused by borrelia burgdorferi due to its impact on mental health.

Schizophrenia/Psychosis and Toxoplasma gondii

Toxoplasma gondii in mouse ascitic fluid DPDxThe idea of the “Crazy Cat Lady” is usually associated with spinsterhood or as an animal hoarder. Recent research have shown a link between childhood cat ownership and the development of schizophrenia later in life. This association is due to Toxoplasma gondii (T. gondii), the most common parasite in developed nations. Studies have shown those with schizophrenia or bipolar disorders have had a greater exposure to cats in childhood [1].

Toxoplasma gondii is a protozoan parasite, with cats being the only known definitive hosts. Humans can become infected by either eating undercooked meat infected with cysts, ingesting food or water contaminated with cat feces, blood transfusion or organ transplantation, or from the mother to the fetus. In humans, the parasites forms tissue cysts, most commonly in skeletal muscle, myocardium, eyes, and especially the brain; and usually remain throughout the life of the host [2].

Cases of toxoplasmosis in adults and AIDS patients are associated with delusions and hallucinations [3]. The brains of those with schizophrenia show evidence of change with its structure and function. Neuroimaging findings of schizophrenia usually show enlarged lateral cerebral ventricles. T. gondii has a known affinity for brain tissue, which can infect the perinatal brain of infants, and may consequently lead to schizophrenic manifestations in adulthood. Glial cells in the brain such as astrocytes are selectively affected and decreased in numbers. In addition, animal studies have shown that the parasite affects the levels of dopamine, norepinephrine, and other neurotransmitters [4].

Preventing infection includes cooking food to safe temperatures, peeling or washing fruits and vegetables thoroughly before consumptions, and avoiding drinking untreated water. To reduce risk from cats, it is important not to feed them raw or undercooked meats and change the litter box daily. If you are pregnant or immunocompromised, avoid changing the cat litter if possible, keep cats indoors, and avoid handling stray or new cats. The antipsychotic haloperidol and mood stabilizer valproate have shown to be the most effective in inhibiting Toxoplasma growth, with Valproate working synergistically with haloperidol and trimethoprim [2].

Manic episodes and Bipolar and the Influenza Virus

InfluenzaMost people are familiar with the common flu caused by the Influenza virus. It can spread by coughing, sneezing, and touching surfaces contaminated by the virus. Common symptoms include: runny nose, sore throat, coughing, headache, fever, and fatigue [5]. What is not usually discussed is the association with Bipolar disorders. An NIH-funded study showed pregnant mothers exposed to the flu was also associated with an increased risk of the unborn child to develop a bipolar disorder (BD) as an adult [6].

A previous study has documented the risk of Bipolar disorder increase during each period of pregnancy. Other data had explored the role of the glycoprotein reelin, which helps in neuron positions in the cortex. Those with Bipolar disorder were found to have significantly decreased amounts of reelin in BD patients. Animal studies showed reduced reelin-positive cells in mice infected prenatally with influenza. It has also been shown that there has been an association with greater vulnerability to influenza among mothers with psychiatric disorders.

An old article presented a possible connection with Influenza and the Locus Ceruleus in the upper pons, the part of the brain that contains the largest aggregate of norepinephrine-bearing neurons in the central nervous system [7]. The viral component neuraminidase possibly interferes with sialic acid on Na/K ATPase and disrupts the gradient needed for the Norepinephrine Transport reuptake to work properly. The inhibition of the reuptake of norepinephrine shares the same features as the effects of cocaine: euphoria, increased mental and physical activity, decrease appetite, and decrease sleep; similar to mania and hypomania.

Prevention against the Flu include getting vaccinated, which takes about two weeks for protection to set in. Antivirals such as oseltamivir (Tamiflu) and zanamivir (Relenza) are recommended for treatment. Mood stabilizers are used for Bipolar Disorders such as lithium, valproate, carbamazepine, lamotrigine, oxcarbazepine [5].

HIV-Related Depression

Date: ?? Courtesy Dr. A. Harrison; Dr. P. Feorino This thin-section transmission electron micrograph (TEM) depicted the ultrastructural details of two ”human immunodeficiency virus” (HIV) virus particles, or virions. A member of the genus Lentivirus, HIV is separated into two serotypes, HIV-1 and HIV-2, and is the cause for the disease known as acquired immunodeficiency syndrome, or AIDS. This virus may be passed from one person to another when infected blood, semen, or vaginal secretions come in contact with an uninfected person’s broken skin or mucous membranes*. In addition, infected pregnant women can pass HIV to their baby during pregnancy or delivery, as well as through breast-feeding. People with HIV have what is called HIV infection. Some of these people will develop AIDS as a result of their HIV infection. What is AIDS?AIDS stands for Acquired Immunodeficiency Syndrome.Acquired – means that the disease is not hereditary but develops after birth from contact with a disease causing agent (in this case, HIV).Immunodeficiency – means that the disease is characterized by a weakening of the immune system.Syndrome – refers to a group of symptoms that collectively indicate or characterize a disease. In the case of AIDS this can include the development of certain infections and/or cancers, as well as a decrease in the number of certain cells in a person’s immune system.A diagnosis of AIDS is made by a physician using specific clinical or laboratory standards.Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS), the advanced stage of infection. The virus impairs the body’s immune cells and over time affects the body’s defenses against infections and certain cancers. HIV is spread commonly through contact with infected bodily fluids. As the infection progresses, common symptoms include swollen lymph glands, frequent fevers, night sweats, weight loss, constant fatigue, diarrhea, and white spots in the mouth [8].

Brain-derived neurotrophic factor (BDNF) in the hippocampus plays a role in protecting neurons and is essential for long-term memory. Initially, neurons release proBDNF which is then cleaved by certain enzymes to produce mature BDNF. BDNF helps in nurturing brain neurons. Recent evidence have shown low levels of BDNF in the blood correlate with severe Major Depression Disorder (MDD) [9].

HIV has a protein on its surface called gp120, which plays a role in binding to CD4 cells. The viral protein gp120 causes apoptosis of brain cells by interfering with the action of furin and tissue plasminogen and leads to interference with the cleaving of proBDNF, which is toxic to the neurons. High level of proBDNF leads to the shortening of axons that normally connects other neurons to each other, known as “synaptic simplication.” This can also be found in old age associated with dementia. Antidepressant treatment promotes increased BDNF activity as well as several forms of neuronal plasticity, including neurogenesis, synaptogenesis and neuronal maturation.

Common treatments for depression include cognitive behavioral therapy, Selective serotonin reuptake inhibitor (SSRI) and Serotonin and norepinephrine reuptake inhibitor (SNRI). It is important to avoid dangerous drug interactions with people with HIV/AIDS [8].

Lyme Neuroborreliosis

Shown in this darkfield microscopy (400x mag) are the spirochetal bacteria known as Borrelia burgdorferi, the bacterium responsible for Lyme disease.Borrelia burgdorferi are helical shaped bacteria and are about 10-25µm long. These bacteria are transmitted to humans by the bite of infected deer ticks and caused more than 23,000 infections in the United States in 2002. 1993 L-206, Lyme Disease, 1993 CD_100_DH/ 018 http://www.cdc.gov/ncidod/dvbid/lyme/ CDC – Div. of Vector-Borne Infectious Diseases: Lyme Disease Home Page http://www.cdc.gov/ncidod/diseases/submenus/sub_lyme.htm CDC – National Center for Infectious Diseases – Lyme Disease

Borrelia burgdorferi is the most common human tick-borne disease in North America. Initially, the bacteria travel from the gut of the tick to the salivary glands during its feeding process. The first stage of illness begins after the invasion of the skin and causes the classic “Bulls Eye” erythema migrans. The second stage affects the skin, joints, nervous system, and heart within weeks two months after the initial infection. If the disease is not effectively treated, damage to the joints, nerves, and most importantly the brain may develop within months or years [10].

It is still a matter of debate how the bacteria passes through the blood-brain barrier, whether it is due to penetration of the spirochetes between the endothelial cells or direct transcellular passage. The bacteria definitely enter into the cerebrospinal fluid. The bacterial component, Outer Surface (lipo)Protein A (OspA) of Borrelia burgdorferi was found to be essential for the colonization and survival within tick midguts. The antigen OspA adheres to galactocerebrosides on the glial cells. OspA induces apoptosis and astrogliosis, damaging brain cells. Autoimmune mediated mechanisms such as “molecular mimicry” can also lead to neural dysfunction [11].

This widespread attack of the brain in late-stage Lyme disease causes multiple cognitive losses and psychiatric illnesses: memory impairment or loss (brain fog), dyslexia and word-finding problems, visual/spatial processing impairment, slowed processing of information, psychosis, seizures, violent behavior and irritability, rage attacks, anxiety, depression, panic attacks, rapid mood swings that mimic bipolar (manic/depression), obsessive compulsive disorder (OCD), sleep disorders, attention deficit/hyperactivity disorders, autism-like syndromes [12].

Reducing exposure to ticks is the best defense against Lyme disease, as well as Rocky Mountain spotted fever, and other tick-borne infections. Antibiotics commonly used for oral treatment include doxycycline, amoxicillin, or cefuroxime. Those affected with neurological illnesses may need intravenous treatment with drugs such as ceftriaxone or penicillin. It has been found that severe neuropsychiatric illnesses can often be treated with multi-system treatment targeting Lyme disease [10].

Conclusions:

The main cause of these common psychiatric disorders is still unknown. The pathogenesis causing by these bugs are still under investigation and it is controversial whether infectious diseases are a major player in mental health. In addition, the individual genetic predisposition, the state of the immune system, the dose, the virulence of the infecting strain, the timing, and part of the brain infected can all play a role on the manifestation of psychiatric illnesses.

From a public health viewpoint, it will be useful to better understand the role of infection to help improve the treatment and prevention and reduce the amount of issues usually associated with mental illnesses, such as the morbidity, mortality, stigma, and way of life. It is important for health care professionals to address the problems of infectious diseases and should also explore the chances of an infection as a cause of psychiatric illnesses. Better communication among infectious disease and mental health professionals, as well as additional training, will be needed to better understand harmful pathogens manifesting themselves as neuropsychiatric disorders.

References:

  • Torrey, E. F., & Yolekn, R. H. (2003). Toxoplasa gondii and Schizophrenia. Emerging Infectious Diseases, 9(11), 1375-1380.
  • Toxoplasmosis. (2013, January 10). Retrieved from CDC: http://www.cdc.gov/parasites/toxoplasmosis/
  • Israelski, D. M., & Remington, J. S. (1988). Toxoplasmic encephalitis in patients with AIDS. Infection Diseases Clinical North America, 2, 429-445.
  • Halonen, S. K., Lyman, W. D., & Chiu, F. C. (1996). Growth and development of Toxoplasma gondi in human neurons and astrocytes. Journal Neuropathology, 55, 1150-1156.
  • Influenza (Flu). (2015, September 15). Retrieved from CDC: http://www.cdc.gov/flu/index.htm
  • Parboosing, R., Bao, Y., Shen, L., Schaefer, C. A., & Brown, A. S. (2013). Gestational Influenza and Bipolar Disorder in Adult Offspring. JAMA Psychiatry, 70(7), 677-685.
  • Maurizi, C. P. (1985). Influenza and Mania: A Possible Connection with the Locus Ceruleus. Southern Medical Journal, 78(2), 207-209.
  • HIV. (2015, September 14). Retrieved from CDC: http://www.cdc.gov/hiv/default.html/
  • Bachis, A., Avdoshina, V., Parsadanian, M., & Mocchetti, I. (2012). Human Immunodeficiency Virus Type 1 Alters Brain-Derived Neurotrphic Factor Processing in Neurons. The Journal of Neuroscience, 32(28), 9477-9484.
  • Lyme Disease. (2015, August 14). Retrieved from CDC: http://www.cdc.gov/lyme/index.html
  • Rupprecht, T. A., Koedel, U., Fingerle, V., & Pfister, H. W. (2008). The Pathogenesis of Lyme Neuroborreliosis: From Infection to Inflammation. Molecular Medicine, 14(3-4), 205-212.
  • Nields, J. A., Burascano, J., Liegner, K., DelBene, D., & Liebowitz, M. (1992). The Neuropsychiatric Manifestations of Lyme Borreliosis. Psychiatric Quarterly, 63(1).
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