Toxoplasma gondii in the crosshairs

Source: PsychCentral

Today, Monday 10th October 2011, is World Mental Health Day. It's all about raising awareness about mental health issues. It is quite timely that this years theme is 'Investing in mental health' on the back of the quite startling figures recently published about the numbers and cost (personal and financial) of mental ill-health and the relative lack of funding and research on what causes it and what to do about it.

Anyway, I commerate the day with this post on schizophrena and an old friend.

This is not the first time that the topic of Toxoplasma gondii has graced this blog and probably won't be the last time either. What is perhaps so fascinating about this parasitic protozoa is its single-minded drive to survive (and replicate) and, as a result, its ability to affect animal behaviour by whatever mechanism.

Fine if you are a rodent I hear you cry. But when it comes to human beings, much of the recent chatter about T.gondii has been on its speculated links to conditions like psychosis, mood disorders and, in extreme cases, suicide. Presentation of schizophrenia spectrum conditions and the risks associated with T.gondii infection have also figured fairly prominently in the various discussions as a result of studies like this one and this one from Faith Dickerson and colleagues. A recent study by Pedersen and colleagues* published in the American Journal of Psychiatry has confirmed an association between T.gondii infection and risk of schizophrenia. Association is one thing; causation is another. I note that Dr Emily Deans over at Evolutionary Psychiatry has just posted about this study also.

The facts and figures:

• IgG-antibodies specific to T.gondii were measured in over 45,000 women in Denmark giving birth between 1992 and 1995.
• Women were followed up until 2008 for the presence of a schizophrenia spectrum condition.
• A positive association between T.gondii antibody level and risk of schizophrenia was found; with risk varying according to the strength of the antibody response. The overall risk was 1.68, although where antibody levels were highest, that rose to 1.73.

The conclusions from the study was that where antibody levels to T.gondii were highest so the risk of schizophrenia was highest.

There are some interesting points to take from the cumulative research on T.gondii. Not everyone who is infected with this little scoundrel will go on to develop schizophrenia or other conditions. Obviously there are other factors also at work. The immune system is the first place to look; how our bodies handle such infections, viruses, bacteria and how genes and environment might interact either in a protective or facilitative fashion. I touched upon this briefly with my post on the C4B null allele in relation to autism and a few other conditions. I note also this recent publication from Whitmarsh and colleagues** published in the journal Cell Host & Microbe which suggested that knockout mice (is this the right term?) might more frequently succumb to T.gondii infection when specific cytokine signalling molecules are absent; one factor probably among many. It is not as straight-forward as to say this molecule does this and this one does this; more likely a combination of multiple factors coupled with a cascade effect confer protection or not.

So there you have it, more evidence for the influencing factor of environment on our behaviour. Makes you wonder whether we should be looking more closely at some of the treatments for T.gondii and any potential onward effects for psychological symptoms? Or do we already have our treatment measures?

* Pedersen MG. et al. Toxoplasma infection and later development of schizophrenia in mothers. Am J Psychiatry. August 2011.
** Whitmarsh RJ. et al. A critical role for SOCS3 in innate resistance to Toxoplasma gondii. Cell Host & Microbe. September 2011.

C4B null allele and autism

Big names in autism research was covered in one of my recent posts on this blog. At the time I did not want to name names, despite focusing on Prof. Sir Michael Rutter and his various observations on autism research and what we think we know about autism. In this post, I am going to name a name: the late Reed Warren and his various research on the C4B null allele in connection to autism.

I met Reed Warren only once, very early on in my autism research career. He was a Professor of Immunology (I think) based at Utah State University in the United States. I faintly remember that at the time of meeting him he was not in the best of health and sadly passed away not long after our meeting at a conference we were both attending. At that stage in my career, I will admit that whilst aware of his work, I did not fully understand the implications of it and how it fitted into my little corner of autism research. After doing a bit of reading around the topic over subsequent years, I now feel as though I can describe and discuss, albeit perhaps not with the same authority as Warren and his colleagues.

Here goes: what is a C4B null allele?

Well, we start at the major histocompatability complex (MHC) and its link to the immune system and its regulation. Within the genetic region occupied by the MHC, several genes for the complement proteins are found including the C4 genes which encode for the C4 protein. The C4 glycoprotein appears in two forms: C4A and C4B as a function of the C4A and C4B genes. Both versions of the C4 protein are similar in function and structure but also have some distinguishing features from each other.  The C4A and C4B genes are very polymorphic; that is there are various versions of the gene switched on or off which function to varying degrees depending on heterozygoisty or homozygosity. There is a good overview of heterozygosity here and its importance for genetic diversity; basically we all have two copies of a gene as a function of our paired chromosomes and depending on whether or not a gene is expressed the same or differently on each chromosome in that pair will describe the zygosity. It is quite possible for a person to carry what's called a null allele for the C4A and/or C4B genes, which basically means that the respective gene makes little or no C4A or C4B protein. If a person is homozygous for the null allele (the gene on both chromosomes is switched off), it means that the gene should make absolutely no protein. I know I have probably not done justice to the concept of the C4B null allele with this brief description, but as with many things related to genes, such things are never easy to interprete or explain.

The C4B null allele has cropped up a few times in the research literature in connection to things like type-1 diabetes, coeliac disease and cases of recurrent spontaneous abortion. It is perhaps with autism in mind, that most of the research has been done as witnessed by papers here, here and here. OK I hear you say, so what if a C4B null allele is present, what does it mean?

Well, this is where a degree of speculation takes over, as once again the limits of my competence are tested. It is important to realise that the presence of a C4B null allele is not exclusively tied into autism. Like many genetic findings, the relationships are complex and overlapping with other conditions and asymptomy. Warren and colleagues in their papers hinted at this in their 1991 paper, and instead suggested that the presence of a C4B null allele might lay the foundations for a genetic predisposition, compounded by other issues with the immune system and exposure to one or more pathogens. Their later paper published in 1996, whilst taking into account the relatively small participant numbers included, noted the greatest frequency of one (or both?) C4B null allele was actually found in cases of reading disorder (67.7%), followed by ADHD (56.5%) and then autism (48.9%) (controls = 20.3%). This would suggest that the C4B null allele may play a role in autism, but also in these other conditions.

Following the 'game changer' that was the results of the California Autism Twin Study, I think our view of genes and autism is undergoing a bit of a shift at the moment. Whilst being no great lover of the 'autism is totally genetic' hypothesis still being banded around by some, the C4B null allele and other genetic stories are still worthy of some consideration in some cases of autism. Indeed only very recently has the C4 gene come up again in relation to some speculations on mycobacterium paratuberculosis and autism.

In memory of Reed Warren and his contribution to autism research.