From Sjogren's to Leaky Gut to Menière's to Labyrinthitis - a proposed theory

I have come across a few published articles that cover the high incidence of systemic autoimmune diseases in patient's with Menière's Disease, for example [1, 2], but I always wondered if the other way around could also be a possibility. I mean, one of the health disturbing aspects I have seen reported in Sjogren's patients has to do with events of labyrinthitis (inflammation of part of the inner ear) or pressure put in the inner ear by a very inflamed parotid gland that can trigger vestibular disturbance (i.e., related to the inner ear and sense of balance). However, since Sjogren's is so intrinsically related to metabolism and diet, I have also learned of the nefarious effects caused by certain foods and beverages in a patient's balance, vestibular 'equilibrium' and an impaired digestive tract.

It is easy to establish a chain of consequences that is potentially triggered at any point of the affected physiological system, one that in a healthy person can be counteracted and re-established to normality, but that in an autoimmune one will have to be compensated with potential biological actions that can, on their own, eventually initiate particular imbalances elsewhere in the system. 

However, autoimmunity (where Sjogren's sits as a syndrome) appears to be quite associated with Menière's disease (a pathophysiology marked by vertigo, tinnitus, high pressure felt at the inner ear, and in grave cases even resulting in hearing impairment) [1]. Menière's can play episodically through events usually marked by inflammation at an associated contiguous point, even resulting in potential bilateral vestibular hypofunction (in the worst scenarios). But just as Sjogren's syndrome, also Menière's disease is a chronic condition, hence persistent and recurrent, where the associated vertigo episodes can last from a only a few minutes to excruciating long hours. Now imagine the impact on the performing of regular activities such as driving, operating machinery, walking, etc.

Where some doctors might immediately resort to prescribing prochlorperazine maleate or any other typical phenothiazine indicated for severe nausea, from a personal perspective a patient must also learn how to identify the triggers that typically promote the onset of such vestibular disturbance. In different examples to me presented, I had the chance to read that this can be very closely associated to dietary options alongside the typical promoters, such as stress, anxiety, opportunistic viral infections that take advantage of structurally-compromised tissues, and the consumption of desiccants (such as alcohol, spicy foods, etc.).

Add to all this the still quite abstract concept of leaky gut, a disorder that has not yet been fully clinically accepted and medically characterised, but one that it is thought to involve cracks in the intestinal tissue that will allow the passage of unexpected macromolecules to the blood stream... molecules that due to their size, composition and complexity were not supposed to be allowed in the circulatory system, and that will, therefore, promote physiological disturbance. It is extremely difficult to find literature to support the idea of a leaky gut, but the same people who have been blaming gluten for several metabolic and physiological ailments have now turned (no personal judgement here at all!) to the idea of a leaky gut - as the portal to disarray. From within a list of supposed complications one can identify the multifactorial Menière's disease [3]. And considering what the authors also debate, i.e., "that patients often complain of aspecific gastrointestinal symptoms associated with autonomic dysregulation, frequently outweighed by the otological manifestations", a recurrent cycle of afflictions is theoretically hereby established.

In a way, and as suggested in the image that I have edited and enclosed in the post, the metabolic dietary stressors will trigger a reinforced imbalanced immune response, that is already appanage of an autoimmune disease patient. However, in association with a debilitated gastrointestinal mucosa, be it in the stomach (as it occurs typically with reflux or H. pylori infections, for example) or at the intestinal tissue, the molecules unexpectedly absorbed into the bloodstream will add to the inflammatory dynamics and  this will potentially increase the implications of ongoing inflammation at the vestibular domain. Ergo, making the vestibular tissues even more vulnerable to opportunistic viral infections, and affecting the profile of the naturally-occurring crystals in the inner ear's liquids (the endolymph and perilymph), consequently affecting the audiovestibular moiety, adding to the incidence and seriousness of the reported "dizziness, generalised, imbalance, ataxia, motion intolerance, positional vertigo, oscillopsia, and episodic vertigo" [2].

In that sense, it is my personal belief that dietary changes need to account for the supposed 'leakiness' of the gut, and might be able to help reduce (not cure!!!) the episodic occurrence of inflammation that affects equilibrium in an autoimmune patient. What do you have to say about it? Does it sound feasible?

[1] Gazquez, I., Soto-Varela, A., Aran, I. et al (2011). "High Prevalence of Systemic Autoimmune Diseases in Patients with Menière's Disease". PLoS One, 6(10): e26759.

[2] Girasoli, L., Cazzador, D., Padoan, R et al. (2018). "Autoimmunity and Otolaryngology Diseases - Update on Vertigo in Autoimmune Disorders, from Diagnosis to Treatment".  Journal of Immunology Research, pp. 1-16.

[3] Berardino, F., Zanetti, D., Ciusani, E. et al (2018). "Intestinal permeability and Ménière's disease". Am J Otolaryngol, 39(2), pp. 153-156.

Original post photo by Omid Armin on Unsplash

Why do pandemic viral infections come in waves?

Hello readers and welcome to yet another very short post. I have been very busy over the past months, can barely make it to write anything, especially when considering the fact that I am still in the early stages of my book on Nosocomial Infections. A book that was planned to be written in one year (2019) and published for free as an online project on the following year (2020); but this pandemic we all know just forced me to postpone due to a range of life restrictions/lockdowns.

Even though I struggle like never before to even read the bear minimum for keeping myself afloat in this immense pool of information that is Life Sciences, I don't wish to abandon this project altogether. It is important for my personal and professional education, and as long as there are others reaching out to me and reading my posts, I believe the knowledge I acquire and share can be, and is indeed, relevant for other intrepid scientific minds.

Hence, I accepted that the ritual of posting in this blog might be affected in periodicity, but cannot be disregarded at all. I will eventually complete the last post (immediately before this one) where I am still trying to find the time to adequately read through my friend's article (don't want to be lenient with that); but I also want to start posting a bit more on The Toxicologist Today. I then came up with the conclusion that short answers to immediate questions that suddenly populate my brain, due to professional requests or just personal doubts I eventually come across with, are the best way to keep in constant contact with you guys. 

So, whenever a topic comes to my mind or emerges from a  natural doubt I might have, I will share it with all of you for awareness, simply because it might be an interesting subject also playing in your mind! But don't worry, I'll make it short (way shorter than this post :D), clear and concise, and I'll make the referencing also short, straightforward, but robust (with significant reliable studies/institutions behind them).

Hope you like it. Shall we start? This one has been assaulting me for quite some time...

Why do pandemic viral infections come in waves?

Apparently pandemic viral infections comprise 6 phases of alertness, as per the World Health Organisation (WHO). And throughout the post-peak period, the strength of the pandemic disease will have been reduced in developed countries with appropriate health surveillance. It will do so until its infectivity proneness has dropped below the former peak registered levels [1]. This means that after the peak period one witnesses a decrease of pandemic activity but only until the virus regains a new viral infectivity/potency due to natural mutations that will bring infection to yet another peak level, until herd immunity starts appearing and a certain dormancy of infectivity is observed. The different peaks/waves can be distanced by many months and relaxation of control measures can be irresponsible, depending obviously on the strength and adequacy of the available scientific responses.

In a nutshell, the first wave results in deaths and disability linked to the viral infection itself; the second wave impacts on subjects who are volatile in the medium-term as a result of failures in the approach during the first wave; and the third wave reveals the consequences of the "virus on the social determinants of health and its effects on the next generation", as per Fisayo and Tsukagoshi (2020),  [2].

[1] About Pandemic Phases, World Health Organisation, [https://www.euro.who.int/en/health-topics/communicable-diseases/influenza/data-and-statistics/pandemic-influenza/about-pandemic-phases], last access on the 02Jun2021, last update unknown 

[2] Fisayo, T, Tsukagoshi, S. (2020). "Three waves of the COVID19 Pandemic". Postgrad Med J, 97, pp. 332.

Photo kindly provided by Erik Mclean on Unsplash

How easy is it for viruses to mutate?

It is a pleasure to be back, and believe me it hasn't been easy being away for so long. However, in all honesty, my absence wasn't result of my immediate choice. I have been flooded with work and the current world crisis didn't really help anyone. From having my children under my responsibility 24/7, plus all the extra work that results immediately from living, or better put, adapting to survive in a quarantined existence/lockdown-style, meets new thresholds that none of us had been exposed to before.

I have struggled to write a single line but I have struggled a lot more with reading the enormous idiotic and, sometimes, overtly ignorant information spread out in different platforms, covid-wise! I realised that for some questions the official sources out there are quite good, even though, and I remain with my personal view on it, numbers do no immediately add-up.

Information and counter-information got to such ludicrous levels of ignorant presumptuousness that I decided to educate myself directly form few selected sources and experts. But during my self informing I wasn't able to find an adequate simplified explanation that would respond to different aspects of all this covid-19 pandemics. One of such aspects emerged exactly whilst trying to understand how Italy, UK, Portugal and Spain met such different levels of infectiousness and lethality when presented to basically similar approaches and external/internal pressures/strategies. I just couldn't make sense of certain aspects but the one that caught me empty handed was hearing from a specialist in virology that the virus had just mutated from country to country. I can't easily recall who this person was or what organisation was he speaking from, but to be fair it is not my role to criticise these people, let alone try to play a role of key opinion leader on a matter I am not specialised at all. But because I am a curious person with a thirst for knowledge I researched further in order to try and understand how can that be feasible. How mutable is a viral strain? In even more simplified words....

How easy is it for viruses to mutate?

To be able to address this complex question with a simplified answer it is imperative to accurately estimate virus mutation rates, so then one can infer on the individual and particular evolution of the different object viruses. Only then applicable strategies can be designed to control spread, infectivity and foresee a plausible safe future ahead of any epidemic. That was the work of Sanjuan et al (2010) where different methods of estimation (that in their own nature are quite varied and usually fairly complex) were applied [1]. But how can one define mutation rate? Well, the authors defined it as substitutions per nucleotide per cell infection (s/n/c) (so to account for viability rather than just mutations with no biological meaning at all) and corrected for selection bias where applicable and deemed necessary. 

Their observations were quite impressive as the obtained rates stretched from from 10−8 to10−6 (in DNA viruses) and from 10−6 to 10−4 (in RNA viruses) supporting the classic idea of a negative correlation (meaning one decreases when the other increases, and vice-versa) between mutation rate and genome size among RNA viruses and also DNA viruses. In addition, [1] shows that nucleotide substitutions are on average 4 times more frequent than insertions of nucleotides and deletions of nucletotides in the 'viral genome', the usually called 'indels'. But another very useful public tool they came up with is the regularly updated (so they say) virus mutation rate data that one can find at the url: www.uv.es/rsanjuan/virmut [2] with the main objective of providing an easily available, organised and professional data set on viral mutation rates. Just for the sake of curiosity and example, I can tell you that corona virus, as expected, is not part of the studied viruses, and that HIV-1 has a mutation rate of 4.9E-5 (s/n/c) whereas Influenza A virus sits at 4.5E-5 (s/n/c) - both these values are mutation rates per cell infection.

It is easy to understand that not all mutations are biologically effective and significant and that lethality power can actually undermine the relevance of the virus because a virus with a deadly mutation to humans, basically kills rapidly the host on which the virus itself depends on (for viruses are not living beings, they are merely simple algorithms of genetic code that operate not knowing very well in what overall program do they actually integrate - that is how funny and scary viruses are!!!).  If they kill the host quickly, let's say even faster than Ebola kills, the virus would require an immediate host to progress with spreading infection... and in that sense its associated lethality can undermine it's biological success. To avoid disappearing, a virus should be very infectious and lesser lethal! That is my understanding.

But what about their mutation 'strategy'? Apparently there are several types of consequential mutation 'strategies' if we can exaggerate and affirm these things even have a subliminal plan. Basically pure evolutionary and external pressures and forces shape their 'swarming' but apparently, at least in what relates to HIV and Influenza, their mutation is linked to antigenic drift and antigenic shift. The former occurs with a change in aspect of the outer surface protein where the host won't be able to identify the virus, hence an insufficient defensive response takes place; and the latter is defined by 'fusion' of different types of the same virus merging and becoming a new very different type from its root strains - that will catch the host by surprise and their limited antibodies will not be able to cope with the new profile of viral infection [3] - the 2003 zoonotic H5N1 influenza A virus epidemic that infected humans is a good example, but luckily one with limited infectivity/lethality correlation!

The mutational capability and profiling of viruses is a world of knowledge. And not only time is limited but also your patience. So allow me to save these last two short paragraphs to discur on two straight points:

What other factors participate on the mutational rate of viruses? Population density where the highest density (overcrowding) will find successful jumps of viruses from one host to another, more rapidly and more effectively. Also, a virus with longer incubation times associated to what I had explained in the previous paragraphs, lesser pronounced lethality. This will even allow a zoonotic virus to live freely in migratory animals and spread happily to distant geographical points. Biologically clever, isn't it?! But in a nutshell, the best answer to how easy it is for viruses to mutate, can be found in the work of Sanjuan and Domingo-Calap (2016) [4] where the authors state that impressive capacity of some viral strains to adapt to new hosts and environments is strongly determined by their capacity to produce newer viral proteins in a short period of time. As the authors state, the present knowledge of viral mutation rates shows that "viral genetic diversity is determined by multiple virus- and host-dependent processes, and that viral mutation rates can evolve in response to specific selective pressures", as discussed above. Viral mutation rates are programmed and performed by means of polymerase fidelity inclusion, at sequence context, at template secondary structure, at cellular microenvironment, through replication mechanisms, during proofreading and/or during access to post-replicative repairing,  by means of virus-encoded diversity-generating elements or even by host-encoded cytidine/adenine deaminases [4]. 

What is the mutational rate of SARS-CoV-2? The jury is unfortunately still out there and so will be for a long time, but I suspect that a recent article by Tang et al (2020) [5] offers the best most up-to-date original information we have accomplished so far (though naturally limited, as you may well understand). They propose that SARS-CoV-2 can be classified in two major lineages (L and S) defined by just two tightly linked SNPs (single nucleotide polymorphisms) at positions 8,782 (orf1ab: T8517C, synonymous) and 28,144 (ORF8: C251T, S84L). Their mutational load analysis reports that "the L lineage had accumulated a significantly higher number of derived mutations than S lineage". Moreover, they also found merely 4% variability in genomic nucleotides between SARS-CoV-2 and a used-for-reference "bat SARS-related coronavirus (SARSr-CoV; RaTG13)", and the identified "difference at neutral sites was 17%", pointing towards the idea that, as the result of different selective pressures, "the divergence between the two viruses is way larger than initially thought. 

[1] Sanjuan, R., Nebot. M. R., Chirico, N., Mansky, L. M., Belshaw, R. (2010). "Viral Mutation Rates". Journal of Virology, 84(19), pp. 9733-9748.

[2] Viral Mutation Rates, Institute for Integrative Systems Biology (I2SysBio), [https://www.uv.es/rsanjuan/virmut], last access on 29th of June 2020, last updated on 2010.

[3] Viruses and Evolution, The History of Vaccines - An Educational Resource by the Colleage of Physicians of Philadelphia, [https://www.historyofvaccines.org/content/articles/viruses-and-evolution], last accessed on 29th of June 2020, last updated on the 10th of January 2018.

[4] Sanjuan, R., Domingo-Calap, P. (2016). "Mechanisms of viral mutation". Cell Mol Life Sci, 73(23), , pp. 4433-4448.

[5] Tang, X., Wu, C., Li, X. et al (2020). "On the origin and continuing evolution of SARS-CoV-2". Natural Science Review, 7(6), pp. 1012-1023.

Post photo by CDC on Unsplash.

Unzipping Zika, The anatomy of any virus

I never intensely wrote about viruses on this blog, basically because I am no expert in viruses. I have loads of them in my computer, some actually ended up messing up with my hard-drive so badly that I had to purchase a brand new one. Recently, I got to stay in bed for a week with a stupid Influenza variation that ruined my energy and reduced me to tears. I survived both events, the computer infection and the flue one. But as I rise from the death to go back to my thesis writing and job hunting, as I always do every single morning after dropping off my little one in the nursery, the world announces me that I shall not rest my defenses for another virus is coming.

Some time ago there was Ebola. The cacophony of its name actually makes me laugh and it is such an interesting virus that can trigger many plot ideas for cinema motion pictures. But we apparently survived that. Far before that we had A type Influenza, the hens and the pigs were conspiring to take over what had been rightfully owned by the human race. We managed to survive that. But now there is something worse, something that does not want to mess up with the birds and the Suina, doesn't want to emerge from the tombs of African forests, it comes from the sunny landscapes of South America with more Sambuca than Samba, and is making our heads spin with its transmission features.

Because I am not a virus expert I'd like to understand the basics before jumping to the hard matter on the news. And when everyone is talking about how Zika, this new virus from the warm pastures of South America, can make the human babies suffer of microcephaly, well!... You want to know all there is to know. So I thought that for those who struggle like me in understanding a few of the basics that reporters so intelligently babble in Nobel-Prize-type-short-interventions, why not compiling a few bits of info first:

In what consists a virus?

Viruses are obligate intracellular parasites and can only reproduce inside a host cell. They consist of nucleic acids enclosed in a protein coating and eventually a membranous envelope. Viruses do not possess enzymes to degrade stuff or ribosomes to produce proteins. They are like transposons that travel around the genome like Harley Davidson easy-riders.

How does a typical virus look like?

Viruses carry DNA or RNA?

They can carry single stranded or double stranded, RNA or DNA!, and that is what actually defines their nomenclature... RNA virus or DNA virus.

                              Do they only infect people?

            They can also infect animal, plants and bacteria (these are quite complex in nature and structure).

                              Why is that they kill the cells?

            Because for viruses to reproduce they use lytic and lysogenic cycles. The lytic cycles are typical of the strongest viruses, usually kill the host cell and are accompanied by a very adaptable genome that fights restriction nucleases bacteria might produce. The lysogenic cycles consist on softer processes where the host cell is not destroyed. Some phages can actually use both reproductive systems.

             What are viruses looking for in the host cells?

            The very same we humans look everywhere, the right conditions to survive and have fun. The host cell provides energy in the shape of ATP, also amino acids, ribosomes and enzymes the virus doesn't have, and the good old nucleotides (the building blocks of the nucleic acid production that also sustain the very nature of virology).

                           Why do some viruses reappear?

            Well some are just very good in keeping dormant until the right conditions are set for them to show up again, like the herpes virus. The herpes virus has an envelope deriving from the nuclear membrane, it becomes integrated in the host cell genome as a provirus and when the right stressful situations occur, the virus emerges for the festival. The main route of infection is propelled by the envelope of the virus that can attach and invaginate in the cell membrane lipid bilayer, then the endoplasmatic reticulum of the cell will provide proteins that only help the cell get worse and worse.

        Is there a virus hardcore division, like the real bad guys?

            Ohhh yesss! The retroviruses have been the Grim Reaper of rock stars from the early 80s like mad killers. These are more complicated to explain because their genetic information flow in the reverse direction!

                                 What are the Premier League and the 

                Conference Leagues of Viruses in animals?

                                Check the image below and you will have your answer.

                How do viruses actually destroy the cell?

            Essentially in three major ways: 1) some by telling the host cells to release hydrolytic enzymes, 2) some by telling the host cells to produce toxins that promote disease, and 3) others already have these toxins in their envelopes and just need to deliver the bad messages straight in.

                  Is there any other smaller type of viruses?

            Yes, shall we call it the Tiny Tiny Division, constituted by Viroids and Prions. Viroids are smaller and simpler than viruses and typically infect plants. Prions are proteinaceous infectious particles and became famous in the 90s for driving cows very very mad crazy!

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Great!, I didn't really tell you anything special about the Zika virus, but in all honesty you know more about it now than you knew before. And that was to build a foundation, the rest will unfold as the world unzips the Zika virus... at least until something more fashionable gets the attention of the media.