What’s the most likely reason that human breast milk has such a high variety of oligosaccharides compared to that of other species?


, , , ,

The statement ‘It is unclear why human breast milk stands out among that of other mammals. It has five times as many types of H.M.O.s as cow’s milk, and several hundred times the quantity. Even chimp milk is impoverished compared with ours‘ is in a recent New Yorker article. Its premise is inaccurate. Published data from 2011 directly contradicts it, specifically, by showing chimpanzee and human milk oligosaccharides (HMOs) are comparably diverse and abundant (see figure below from 1), though HMOs have higher degree of polymerization. Ironically, this paper is authored by University of California, Davis, researchers, including one of the persons interviewed in this New Yorker piece, Bruce German.

Caveats: Problem is this study was conducted on just one milk sample from each species, the monkey and ape milk samples coming from animals in research centers, not in the wild. Not clear if they were fed regulated diet or could forage by themselves. Sole human milk sample used for comparison was from a mother in Gambia, Africa. Obviously since age, diet and genetics are all important factors, milk composition’s known to vary greatly between mothers from different countries. Milk composition also differs greatly at different stages of lactation. Thus we cannot generalize much from what is more or less a case study. An overlapping team also published a 2010 paper comparing milk oligosaccharides from different primates that included more numbers of animals from each species, but unfortunately didn’t include chimpanzees (2). Thus, this data needs to be verified by examining more milk samples from these primates. Would also be interesting, if possible, to compare milk from wild animals with those in research centers.

I was also taken aback to read the following grossly inaccurate generalization in the same New Yorker piece,

‘The number of scientific publications about milk is tiny, compared with the number devoted to other bodily fluids—blood, saliva, even urine. The dairy industry has spent a fortune on extracting more and more milk from cows, but very little on understanding just what this white liquid is or how it works. Medical-funding agencies have generally dismissed it as irrelevant, German said, because “it doesn’t have anything to do with the diseases of middle-aged white men.”’

Sure, there are likely many more scientific publications dealing with blood, saliva and urine compared to milk. After all, they’re easily accessible sources to sample circulation to perform diagnoses, as well to simply study physiology. OTOH, milk is typically only made and secreted by lactating adult female breasts. Can’t use milk to diagnose conditions in children, men and non-lactating women, who can usually provide blood, saliva or urine samples any time during their life. In other words, disingenuous to argue diseases of middle-aged white men preclude research funding for studying milk. By the way, all that greater effort into studying blood has still not yielded an adequate fully synthetic replacement to human plasma, i.e., expense and effort alone don’t dictate outcome. As well, having spent several years on a project that used sheep milk proteins as Antigen* may not make me a milk expert but I know enough to know those statements in the article are gross exaggerations to say the least, for the following reasons.

  • Embarking on that project, I soon discovered and consulted with a nearby world expert on one of those milk proteins. The recently retired Pradman K. Qasba from the Frederick, Maryland, campus of the National Cancer Institute, spent the bulk of his career studying just this one milk protein, Alpha-lactalbumin.
  • Milk’s of considerable interest to evolutionary biochemists interested in how milk components may have evolved as a result of Gene duplication events. For example, sequence comparisons suggest alpha-lactalbumin to be the product of Lysozyme gene duplication, an event that may have occurred around the time Mammals spilt from Birds.
  • Alpha-lactalbumin’s also a protein of tremendous interest to biochemists because it belongs to a select class of very intriguing proteins capable of existing in the Molten globule state.
  • And how could one talk of alpha-lactalbumin and its capacity to assume a molten globule state without mentioning Catharina Svanborg – Wikipedia, the Swedish microbiologist, who since at least 2000 has shown repeatedly in the peer-reviewed scientific literature that HAMLET (Human Alpha-Lactalbumin Made Lethal To Tumors) can apparently kill tumors directly?
  • This is barely scratching the surface of research on just this one milk component. And as recently as March 2012, Catharina Svanborg was an invited speaker at University of California, Davis’ Foods for Health Institute, where the afore-quoted Bruce German works (Dr. Catharina Svanborg Presents her Research on Cancer-Killing Proteins in Human Milk).
  • Also important to note that the study of alpha lactalbumin is inextricably tied to that of milk sugars. Arguably among the most abundant of milk sugars, albeit a disaccharide, not oligosaccharide, Lactose synthesis requires alpha lactalbumin.

A 2012 review on HMOs by Lars Bode helpfully includes a >100 year retrospective (see figure below from 3).

Thus, it doesn’t reflect well on the New Yorker to not have more carefully vetted this science-related article that contains such inaccurate generalizations. Lazy science journalism doesn’t just do disservice to science, no, it’s also dangerous in its potential to further fray the public’s increasingly fragile trust in the scientific enterprise. Anyway, this brief deconstruction suggests to not take some of this article’s assertions at face value.

Differences in milk composition between species are several and well-documented. While primate milk tends to contain greater variety and quantity of oligosaccharides compared to those of ruminants like cows, milk from the latter is abundant in Beta-lactoglobulin, which is completely absent in human milk. Donkey milk contains a greater variety and amount of Omega-3 fatty acid and Omega-6 fatty acid compared to human milk (4), a difference that’s stoking some interest in developing it as a Nutraceutical.

What do such differences mean? At a minimum, they demonstrate exquisite adaptations of milk composition to different selection pressures imposed by specific ecological niches and specific life history-driven demands of babies of different mammalian species. What those different selection pressures specifically are remain speculations at present. Upon reflection, aren’t differences in composition between milks from different species only to be expected? Different mammalian species may need to have different milk components to

  • Prepare their newborn’s gut to be colonized by different microbes, i.e., different milks with different Prebiotic (nutrition) potential accurately reflect the different ecological niche each species occupies. Such differing components would help different microbes to colonize a newborn’s gut as well as help protect against pathogens that each newborn mammalian species would need protection from, obviously something where different mammals likely differ. One way milk sugars could protect against pathogen invasion is by binding to carbohydrate binding proteins, especially on viruses, i.e., functioning as decoy molecules to clear them from the body. For example, human milk glycosaminoglycans can bind to HIV ‘s Envelope glycoprotein GP120 (5).
  • Satisfy different energetic/caloric requirements of different newborn species. For example, calves and foals start to graze and forage by themselves within a few days to few weeks of birth, obviously a drastically different situation from that of human babies. A calf or foal’s nutritional demands on cow or horse milk would thus likely be far less onerous compared to those of a human baby’s on human milk.
  • Account for different Placentation strategies adopted by different mammalian species, account in terms of one species needing to provide post-birth some essential nutrient that another species may already provide in utero. A salient example is greater need for immediate post-birth Colostrum in bovines and equines, which have less invasive epitheliochorial placenta compared to primates, which have more invasive haemochorial placenta. One result of this placentation difference is relative lack of in utero transfer of maternal antibodies in cows, sheep and horses, which is why newborn calves, lambs and foals need to immediately post-birth drink colostrum, their main source of maternal antibodies.

*: Tirumalai Kamala’s answer to What Quora users have patents?


1. Tao, Nannan, et al. “Evolutionary glycomics: characterization of milk oligosaccharides in primates.” Journal of proteome research 10.4 (2011): 1548-1557. https://www.researchgate.net/pro…

2. Goto, Kohta, et al. “Chemical characterization of oligosaccharides in the milk of six species of New and Old world monkeys.” Glycoconjugate journal 27.7-9 (2010): 703-715. https://www.researchgate.net/pro…

3. Bode, Lars. “Human milk oligosaccharides: every baby needs a sugar mama.” Glycobiology 22.9 (2012): 1147-1162. Every baby needs a sugar mama

4. Chiofalo, Biagina, et al. “Comparison of major lipid components in human and donkey milk: new perspectives for a hypoallergenic diet in humans.” Immunopharmacology and immunotoxicology 33.4 (2011): 633-644. https://www.researchgate.net/pro…

5. NEWBURG, DAVIDS, et al. “Human milk glycosaminoglycans inhibit HIV glycoprotein gp 120 binding to its host cell CD4.” J Nutr 125 (1995): 419. https://www.researchgate.net/pro…


What portion of our dietary calories do our gut bacteria consume?


, , , ,

What portion of our dietary calories do our gut bacteria consume? Our guts support a wide array of microorganisms. These must either survive off of our food, or off of bodily secretions made with energy from food (e.g. bile). How much of a typical daily diet is consumed by microorganisms rather than being absorbed by the body?

Is it even possible to consider the caloric consumption by our gut microbes as a separate activity? By implying the Microbiota is imposed upon the human body, this question’s implicit assumption of an us versus them dynamic is problematic to say the least. We can eliminate swaths of human microbiota through antibiotics and try to add others through probiotics but does an autonomous microbe-free human body exist in nature? The human and microbial parts of our body are bound together inextricably. After all, microbes aren’t limited to our gut but encompass other mucosal surfaces such as the respiratory and reproductive tracts, not to mention the ‘largest organ’ in our body, the skin. Thus to ask what portion of dietary calories is consumed by the ‘human body’ versus its ‘microbiota’ is akin to seeking to slice a bowl of water.

That said, energy from diet depends on diet type. Diet type in turn favors stable colonization by certain microbes over others. As we are now discovering almost by the day, to a great extent, microbial metabolism of diet determines caloric yield. Research suggests gut microbiota interact with diet in as-yet not totally deciphered ways to

a) help more efficiently digest food and generate more calories,

b) generate metabolites capable of causing great harm over the long term, for example in cardiovascular diseases, and

c) generate metabolites important for regulating bile acid synthesis, something that may have great bearing in obesity.

A 2016 review by Sonnenburg and Bäckhed (1) is a handy source that summarizes how and what gut microbiota could contribute to such varied aspects of human metabolism.

Generated Primarily By Gut Microbes, Calories Derived From Dietary Fiber Depend On Diet Type

Gut microbes are critical for Dietary fiber digestion through the process of fermentation, which converts this otherwise indigestible material into energy (ATP) optimal for use by the cells in the anaerobic environment of the intestine (1, 2, 3, 4, 5, 6, 7, 8).

  • Fermentation generates Short-chain fatty acid (SCFA) such as acetate, butyrate and propionate.
  • SCFA are important for all manner of normal physiological processes (8, 9).
    • SCFA were estimated to provide 5 to 10% of the calories available for absorption from the typical industrialized world diet that’s fiber-poor, and saturated fat- and sucrose-rich (10).
    • OTOH, plants are the main source of dietary fiber (11). People such as the hunter-gatherer Hazda community in Tanzania consume 7X more dietary fiber (12) compared to that in the prototypical industrialized world diet. Such diets would naturally generate much more SCFA, which would thereby embody a much larger portion of their daily calories, courtesy the work of gut microbes needed for such conversion.

Examined in this light, competition between our body’s human and microbial cells could arise through resource conflict arising from diets from which both can efficiently extract energy (see figure below from 13).

How Microbial Metabolism of Diet Could Influence A Human’s Heart Health

  • High levels of Trimethylamine (TMA) are generated by microbial metabolism of L- Carnitine and Phosphatidylcholine from diets rich in red meat, and cheese, eggs, meats and seafood, respectively.
  • Absorbed into bloodstream from the gut, TMA’s enzymatically oxidized to Trimethylamine N-oxide (TMAO).
  • Some recent high profile studies suggest TMAO could promote Atherosclerosis (14, 15; see figure below from 16).
  • Connection between diet and microbiota is suggested by the fact that microbiota of vegans remained poor producers of TMA, even when they were transiently provided TMA precursors in their diet (15) though we don’t yet fully understand the precise conditions under which TMAO promotes cardiovascular disease.
Microbial Metabolism-Derived Secondary Bile Acids Aren’t Just Detergents That Promote Dietary Fat Absorption, They’re Also Signaling Molecules In Metabolically Important Feedback Loops
  • Gut microbiota modify human host-derived bile acids synthesized by hepatocytes from cholesterol. Originally the idea was these secondary bile acids acted as detergents to help absorb dietary fats.
  • Since the 1990s, however, research has uncovered additional functions in the form of signaling capacity in metabolic pathways. In fact, microbial modification of bile acids could function as a negative feedback loop to reduce bile acid production (see figure below from 17).
  • Altered microbiota are associated with imbalances in this pathway (18, 19), as seen in obesity and Steatosis. This suggests inhibition of bile acid synthesis may not be occurring normally in obese people.


1. Sonnenburg, Justin L., and Fredrik Bäckhed. “Diet-microbiota interactions as moderators of human metabolism.” Nature 535.7610 (2016): 56-64. http://www.nature.com/nature/jou…

2. Grabitske, Hollie A., and Joanne L. Slavin. “Low-digestible carbohydrates in practice.” Journal of the American Dietetic Association 108.10 (2008): 1677-1681.

3. Koropatkin, Nicole M., Elizabeth A. Cameron, and Eric C. Martens. “How glycan metabolism shapes the human gut microbiota.” Nature reviews Microbiology 10.5 (2012): 323-335. http://www.ncbi.nlm.nih.gov/pmc/…

4. Flint, Harry J., et al. “Microbial degradation of complex carbohydrates in the gut.” Gut microbes 3.4 (2012): 289-306. http://www.tandfonline.com/doi/p…;

5. Boutard, Magali, et al. “Functional diversity of carbohydrate-active enzymes enabling a bacterium to ferment plant biomass.” PLoS Genet 10.11 (2014): e1004773. http://journals.plos.org/plosgen…

6. Terrapon, Nicolas, and Bernard Henrissat. “How do gut microbes break down dietary fiber?.” Trends in biochemical sciences 39.4 (2014): 156-158.

7. Larsbrink, Johan, et al. “A discrete genetic locus confers xyloglucan metabolism in select human gut Bacteroidetes.” Nature 506.7489 (2014): 498-502. http://www.ncbi.nlm.nih.gov/pmc/…;

8. Andoh, Akira. “Physiological Role of Gut Microbiota for Maintaining Human Health.” Digestion 93.3 (2016): 176-181.

9. Hijova, E., and A. Chmelarova. “Short chain fatty acids and colonic health.” Bratislavské lekárske listy 108.8 (2007): 354. https://www.researchgate.net/pro…

10. McNeil, N. I. “The contribution of the large intestine to energy supplies in man.” The American journal of clinical nutrition 39.2 (1984): 338-342.

11. Bergman, E. N. “Energy contributions of volatile fatty acids from the gastrointestinal tract in various species.” Physiological reviews 70.2 (1990): 567-590.

12. Schnorr, Stephanie L., et al. “Gut microbiome of the Hadza hunter-gatherers.” Nature communications 5 (2014). https://www.researchgate.net/pro…

13. Wasielewski, Helen, Joe Alcock, and Athena Aktipis. “Resource conflict and cooperation between human host and gut microbiota: implications for nutrition and health.” Annals of the New York Academy of Sciences (2016). http://onlinelibrary.wiley.com/d…

14. Wang, Zeneng, et al. “Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.” Nature 472.7341 (2011): 57-63. https://www.researchgate.net/pro…

15. Koeth, Robert A., et al. “Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis.” Nature medicine 19.5 (2013): 576-585. http://www.imsmp.org/sites/defau…

16. Tang, WH Wilson, et al. “Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk.” New England Journal of Medicine 368.17 (2013): 1575-1584. https://www.researchgate.net/pro…

17. Joyce, Susan A., and Cormac GM Gahan. “Bile acid modifications at the microbe-host interface: potential for nutraceutical and pharmaceutical interventions in host health.” Annual review of food science and technology 7 (2016): 313-333.

18. Parséus, Ava, et al. “Microbiota-induced obesity requires farnesoid X receptor.” Gut (2016): gutjnl-2015. https://www.researchgate.net/pro…

19. Ryan, Karen K., et al. “FXR is a molecular target for the effects of vertical sleeve gastrectomy.” Nature 509.7499 (2014): 183-188. https://www.researchgate.net/pro…

For Further Reading:

1. Krajmalnik-Brown, Rosa, et al. “Effects of gut microbes on nutrient absorption and energy regulation.” Nutrition in Clinical Practice 27.2 (2012): 201-214. http://www.ncbi.nlm.nih.gov/pmc/…

2. Martens, Eric C., et al. “The devil lies in the details: how variations in polysaccharide fine-structure impact the physiology and evolution of gut microbes.” Journal of molecular biology 426.23 (2014): 3851-3865. http://www.ncbi.nlm.nih.gov/pmc/…

3. Blaut, Michael. “Gut microbiota and energy balance: role in obesity.” Proceedings of the Nutrition Society 74.03 (2015): 227-234.


Why does not our body make antibodies against food we intake?


, ,

Making immune responses against food components is part and parcel of normal physiology. Whether outcome is normal or not depends on the type of immune responses (see figure below from Berin, M. Cecilia, and Hugh A. Sampson. “Food allergy: an enigmatic epidemic.” Trends in immunology 34.8 (2013): 390-397. http://icahn.mssm.edu/static_fil…).

  • Normal Immune Responses to Food Antigens: As long as antibody classes such as Immunoglobulin A and IgG4, and T cell responses such as Regulatory T cell predominate, outcome is likely to be benign.
  • Abnormal Immune Responses to Food Antigens: Outcome can be pathology if antibody classes other than IgA predominate, especially Immunoglobulin E antibodies, since Antigen-IgE complexes can bind to specific receptors on cells such as Mast cell, resulting in release of potent chemical messengers such as Histamine, which represents the hallmark of typical allergic immune responses. In the case of food antigens, such outcome results in food allergies.



Is mononucleosis (a.k.a mono) active during winter?



Infectious mononucleosis (IM) is usually caused by the Epstein–Barr virus. Typically, once a person acquires EBV, it stays in their body for life. However, such a person isn’t always infectious (1, 2). Though seasonal changes in IM incidence have been observed in a few studies, they don’t all find peak incidence at the same time of the year, and some studies found no seasonal pattern whatsoever.

Studies that show IM incidence is higher or peaks in spring (defined as March, April, May in the Northern Hemisphere)

  • Oxford, UK, 1954-1956, n = 342 (3). Peak IM incidence from April to July.
  • England and Wales, 1973-1992, n = 4769; Scotland, 1983-1993, n = 3294; England and Wales, Northern Ireland, Eire, Channel Islands, Isle of Man, 1980-1984, n = 74552 (4). Peak IM incidence in March.
  • University of Minnesota college students, USA, 2006-2007, n = 66 (5, 6). Peak IM incidence in March.

Studies that show IM incidence isn’t higher in spring

  • Hospital IM cases, Malmo, Sweden, 1954-1960, n = 424 (7). No clear pattern but slight increase in October.
  • Metropolitan Atlanta, Georgia, USA, 1968, n = 575 (8). Two IM peaks, major one in JanuaryFebruary, smaller one in April-May.
  • 19 colleges across the USA, 1969-1970, n = 2811 (9). No consistent seasonal pattern.
  • Military personnel, Israel, January 1978 to December 1991, n = 590 (10). Peak IM incidence from June to August.
  • Military personnel, Israel, January 1978 to December 2009 (11). Peak IM incidence in August.

Thus, IM doesn’t seem to be always more active in summer. While spring-summer peaks were observed in 2 studies from the UK and one from the USA, 1 study each from Sweden and the USA found no consistent pattern while 2 studies from Israel found a peak in August and one study from the USA in January-February. Not only different peaks in different countries but also different results from 3 studies in the USA.

Though some of these few studies hint at a seasonal disposition to IM, i.e., greater likelihood of spread from infected individuals at some times of the year compared to other times, season isn’t the only factor in IM infectiousness. IM could also spread if a person became temporarily immunosuppressed, under heavy stress or due to vitamin D deficiency for example, two factors that often precede IM symptoms (6). Means can’t go by season alone to avoid getting IM from someone who’s already infected.


1. Epstein-barr | Mononucleosis | About Mono | CDC

2. How Long Is Mono Contagious?

3. Hobson, F. G., Barbara Lawson, and Mary Wigfield. “Glandular fever: a field study.” British medical journal 1.5075 (1958): 845. http://www.ncbi.nlm.nih.gov/pmc/…

4. Douglas, A. Stuart, Tom Brown, and Daniel Reid. “Infectious mononucleosis and Hodgkin’s disease—a similar seasonality.” Leukemia & lymphoma 23.3-4 (1996): 323-331.

5. Balfour, Henry H., et al. “Behavioral, virologic, and immunologic factors associated with acquisition and severity of primary Epstein–Barr virus infection in university students.” Journal of Infectious Diseases 207.1 (2013): 80-88. Behavioral, Virologic, and Immunologic Factors Associated With Acquisition and Severity of Primary Epstein-Barr Virus Infection in University Students

6. Lossius, Andreas, et al. “Season of infectious mononucleosis and risk of multiple sclerosis at different latitudes; the EnvIMS Study.” Multiple Sclerosis Journal (2013): 1352458513505693.

7. Belfrage, S. “Infectious Mononucleosis An Epidemiological and Clinical Study.” Acta Medica Scandinavica 171.5 (1962): 531-541.

8. HEATH, CLARK W., ALLAN L. BRODSKY, and ABRAHAM I. POTOLSKY. “Infectious mononucleosis in a general population.” American journal of epidemiology 95.1 (1972): 46-52.

9. BRODSKY, ALAN L., and CLARK W. HEATH. “Infectious mononucleosis: epidemiologic patterns at United States colleges and universities.” American journal of epidemiology 96.2 (1972): 87-93.

10. Grotto, I., et al. “Clinical and laboratory presentation of EBV positive infectious mononucleosis in young adults.” Epidemiology and infection 131.01 (2003): 683-689. https://www.researchgate.net/pro…

11. Levine, H., et al. “Secular and seasonal trends of infectious mononucleosis among young adults in Israel: 1978–2009.” European journal of clinical microbiology & infectious diseases 31.5 (2012): 757-760.


Why are dengue patients not medically isolated with a mosquito net to prevent mosquitoes from becoming infected and spreading the virus?


, ,

To spread from an infected person, Dengue viruses circulating in their bloodstream need to be picked up by a mosquito that bites them to take a blood meal. In a mosquito-borne disease like Dengue fever, the proposition to Quarantine a Dengue-infected person with Viremia to minimize their chances of spreading the infection to others then makes sense. Question is whether this is feasible. Dengue presents a two-fold problem in this respect (see figure below from Dengue: Guidelines For Diagnosis, Treatment, Prevention and Control Guidelines for Diagnosis, WHO, 2009, page 25. http://apps.who.int/iris/bitstre…)

  • One, Dengue’s clinical symptoms start with acute-onset fever and in that respect it resembles too many other illnesses.
  • Two, Dengue viremia, i.e., viruses circulating in the bloodstream, also occurs precisely during this phase.

In other words, Dengue viruses circulate in the bloodstream and are available to be picked up by a biting mosquito taking its blood meal precisely when there is no specific indication to suggest the person’s ailment is indeed Dengue.

Given how Dengue-induced fever and viremia coincide in time, we could even speculate Dengue virus infection of humans is exquisitely adapted to maximize its potential to spread. The window of opportunity to isolate a Dengue patient at the right time being extremely narrow, perhaps even non-existent, renders the likelihood of being able to do so vanishingly small.


Which vaccines are definitely effective and which ones are more questionable?


Definitely effective‘ vaccines would presumably be ones associated with disease eradication. For e.g., the Smallpox vaccine for Smallpox (1), and Polio vaccine for Poliomyelitis (2, 3). Yes, it definitely bears remembering that diseases that were scourges as recently as the middle of the 20th century are no longer with us either entirely or almost so, thanks largely to vaccines.

The acellular version of the Pertussis vaccine could be considered an example of a less effective vaccine. Several industrialized countries (Australia, Canada, Western Europe, USA) switched to this version from its more effective whole-cell counterpart, largely based on perceived safety concerns. However, 20+ years of data now show pertussis resurgence associated with acellular vaccine usage in countries that switched (4), implying such a change may not have been judicious.

The Influenza vaccine requires annual immunization simply because it is prepared anew each year based on assessments of which flu strains are circulating in that given year. Thus, the main drawback of current flu vaccines is they aren’t universal, i.e., one vaccine doesn’t protect against all or even many flu strains. As well, a Meta-analysis of flu shot efficacy in the US from 1967 to 2011 found they were only 67% efficacious (5). This is partly because flu shot efficacy can vary considerably from year to year, given that the flu vaccine changes from year to year.


1. Baxby, Derrick. “The end of smallpox.” History today 49.3 (1999): 14. The end of smallpox

2. John, T. Jacob, and Vipin M. Vashishtha. “Eradicating poliomyelitis: India’s journey from hyperendemic to polio-free status.” The Indian journal of medical research 137.5 (2013): 881. http://www.ijmr.org.in/temp/Indi…

3. Jafari, Hamid, et al. “Efficacy of inactivated poliovirus vaccine in India.” Science 345.6199 (2014): 922-925. Efficacy of inactivated poliovirus vaccine in India

4. Tirumalai Kamala’s answer to Why is the pertussis vaccine not protecting those vaccinated for pertussis?

5. Osterholm, Michael T., et al. “Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis.” The Lancet infectious diseases 12.1 (2012): 36-44. http://journalsconsultapp.elsevi…


Mosquito usually carries quite infectious virus like Ebola. Do mosquitoes get infected by viruses they transmit?



Thus far, ‘There is no evidence that mosquitoes or other insects can transmit Ebola virus‘ (1). However, several other viral diseases are mosquito-borne. These include Chikungunya virus, Dengue virus, Yellow fever virus, Zika virus, to mention a few. These are transmitted through the bite of infected Aedes species mosquitoes.

Mosquitoes do get infected by the viruses they transmit (See figure below from 2).

As the figure highlights, in addition to successfully replicating in the mid gut, viruses taken in during blood meals face several barriers to productive infection of mosquitoes. These include a) a time constraint in infecting mosquito mid gut epithelial cells, b) successful escape from mid gut epithelial cells after they replicate within them, and c) successful infection and replication within mosquito salivary glands.

There is also evidence of mosquito-to-mosquito virus transmission (3). While mosquito immune responses against parasitic Protozoa such as Plasmodium are quite well-studied (4), mosquitoes can also make immune responses against viruses that infect them. Studies have found specific mosquito mid-gut immune responses against Arbovirus such as Chikungunya, Dengue virus and West Nile fever (see summary figure from 5, 6).


1. Transmission | Ebola Hemorrhagic Fever | CDC

2. Franz, Alexander WE, et al. “Tissue barriers to arbovirus infection in mosquitoes.” Viruses 7.7 (2015): 3741-3767. Tissue Barriers to Arbovirus Infection in Mosquitoes

3. Haddow, Andrew D., et al. “First isolation of Aedes flavivirus in the Western Hemisphere and evidence of vertical transmission in the mosquito Aedes (Stegomyia) albopictus (Diptera: Culicidae).” Virology 440.2 (2013): 134-139. https://www.researchgate.net/pro…

4. Jaramillo-Gutierrez, Giovanna, et al. “Mosquito immune responses and compatibility between Plasmodium parasites and anopheline mosquitoes.” BMC microbiology 9.1 (2009): 1. https://www.researchgate.net/pro…

5. Saraiva, Raúl G., et al. “Mosquito gut antiparasitic and antiviral immunity.” Developmental & Comparative Immunology (2016).

6. Sim, Shuzhen, Natapong Jupatanakul, and George Dimopoulos. “Mosquito immunity against Arboviruses.” Viruses 6.11 (2014): 4479-4504. Mosquito Immunity against Arboviruses


What would happen to humans if they were affected by endogenous retroviruses as a result of xenotransplantation?


PERVs or porcine endogenous retroviruses are present in the nuclei of all pig cells so avoiding their transfer during xenotransplantation is practically impossible (1). If humans did get infected with PERVs from a xenotransplant, they’d need to get treated, same as with other retroviral infections.

  • Rx with standard anti-retroviral drugs would be an obvious choice but which ones are effective against PERVs?
    • Among Reverse-transcriptase inhibitor used in humans, azidothymidine (Zidovudine) showed anti-PERV activity (2, 3). However, since azidothymidine is also quite toxic, it may not be realistically feasible, i.e., safe enough, for someone who’s also simultaneously undergoing immunosuppression, as patients with transplants do, or if used, it may be necessary to use at lower doses, in which case it may not be completely effective.
    • Among newer anti-retrovirals, Discovery and development of integrase inhibitors such as Raltegravir (4) and Dolutegravir (3) have shown potent anti-PERV activity in vitro.
    • Decades of experience in HIV also show that multi-drug therapy, i.e., using anti-retroviral drugs that target different viral pathways, is the optimal approach since it increases efficacy and reduces risk of drug resistance.
  • The cutting-edge Genome editing approach, specifically the CRISPR system can inactivate multiple PERV loci (5). This important proof-of-concept suggests it may be possible to proactively remove PERVs from pig graft tissue prior to transplanting into humans.

It’s also important to assess the likelihood of actual PERV transmission and there’s data to do so since >200 individuals have received some form of pig transplants (mainly pancreatic islets) or exposure (mainly to pig kidney, liver, neuronal or skin cells) in a variety of experimental studies. So far, there’s not a single report of PERV transmission to humans among these recipients (6, 7, see list below from 8).

However, in vitro data from more than one lab shows that PERVs can be transmitted in human cells exposed to pig-derived blood, plasma or cells in culture (9, 10, 11, 12). Thus, though risk to humans is reportedly low (1, 10), nevertheless it’s tangible enough that it needs to be addressed with defined and rational scientific approaches (13, see quote below).

‘In general, it is likely that the development of surveillance techniques might be guided by the ‘‘Precautionary Principle.’’ That is, ‘the risk of xenogeneic infection is generally thought to be low but the deployment of appropriate procedures and assays should not wait until a risk is confirmed’ (World Health Organization. OECD/WHO Consultation on Xenotransplantation Surveillance—WHO. CDS/CSR/EPH/2001.2 (Guidance Document), 2000)’


1. Takeuchi, Yasuhiro, and Jay Fishman. “Long life with or without PERV.” Xenotransplantation 17.6 (2010): 429-430.

2. Qari, Shoukat H., et al. “Susceptibility of the porcine endogenous retrovirus to reverse transcriptase and protease inhibitors.” Journal of virology 75.2 (2001): 1048-1053. Susceptibility of the Porcine Endogenous Retrovirus to Reverse Transcriptase and Protease Inhibitors

3. Argaw, Takele, Winston Colon‐Moran, and Carolyn Wilson. “Susceptibility of porcine endogenous retrovirus to anti‐retroviral inhibitors.” Xenotransplantation 23.2 (2016): 151-158.

4. Demange, Antonin, et al. “Porcine endogenous retrovirus-A/C: biochemical properties of its integrase and susceptibility to raltegravir.” Journal of General Virology 96.10 (2015): 3124-3130.

5. Yang, Luhan, et al. “Genome-wide inactivation of porcine endogenous retroviruses (PERVs).” Science 350.6264 (2015): 1101-1104. http://arep.med.harvard.edu/pdf/…

6. Heneine, Walid, et al. “No evidence of infection with porcine endogenous retrovirus in recipients of porcine islet-cell xenografts.” The Lancet 352.9129 (1998): 695-699.


8. Denner, Joachim. “Xenotransplantation-Progress and Problems: A Review.” Journal of Transplantation Technologies & Research 2014 (2014). http://www.omicsonline.org/pdfdo…

9. Patience, Clive, Yasuhiro Takeuchi, and Robin A. Weiss. “Infection of human cells by an endogenous retrovirus of pigs.” Nature medicine 3.3 (1997): 282-286.

10. Le Tissier, Paul, et al. “Two sets of human-tropic pig retrovirus.” Nature 389.6652 (1997): 681-682.

11. Wilson, Carolyn A., et al. “Type C retrovirus released from porcine primary peripheral blood mononuclear cells infects human cells.” Journal of virology 72.4 (1998): 3082-3087. Type C Retrovirus Released from Porcine Primary Peripheral Blood Mononuclear Cells Infects Human Cells

12. Wood, James C., et al. “Identification of exogenous forms of human-tropic porcine endogenous retrovirus in miniature swine.” Journal of virology 78.5 (2004): 2494-2501. Identification of Exogenous Forms of Human-Tropic Porcine Endogenous Retrovirus in Miniature Swine

13. Fishman, Jay A., Linda Scobie, and Yasuhiro Takeuchi. “Xenotransplantation‐associated infectious risk: a WHO consultation.” Xenotransplantation 19.2 (2012): 72-81. https://www.researchgate.net/pro…


Can an HIV-negative person get Kaposi’s sarcoma?


, , ,

Kaposi’s sarcoma (KS) is not exclusive to HIV infection. Human herpesvirus 8 causes KS. There are 4 known KS variants

  • African or endemic (AKS)
  • Classic or Mediterranean (CKS)
  • Post-transplantation (iatrogenic)
  • AIDS-associated or epidemic (AIDS-KS)

AKS is prevalent in subequatorial Africa, quite aggressive, affecting not just skin but also internal organs. If it involves lymph nodes, as often seen in children and young adults, it can be quickly fatal.

CKS is rare, predominantly affects men (male to female ratio is 10 to 15 versus 1), mainly elderly Eastern European Jewish or Mediterranean men. CKS tumors are slow-growing, mild with lesions mainly in skin of the lower limbs (legs, ankles or soles of the feet).

Post-transplantation (iatrogenic) shows up in organ transplant patients after chronic immunosuppressive therapy. Often lesions are in the mouth (oral mucosa) but also elsewhere including internal organs.

AIDS-KS is the most aggressive type of KS. Unlike the other 3 types of KS, it doesn’t show preferential patterns of localization. Lesions are widely spread across the skin as well as in mouth and internal organs (liver, lung, GI tract, spleen).

Relevant references

1. Régnier-Rosencher, Elodie, Bernard Guillot, and Nicolas Dupin. “Treatments for classic Kaposi sarcoma: a systematic review of the literature.” Journal of the American Academy of Dermatology 68.2 (2013): 313-331.

2. Sgadari, Cecilia, et al. “Pharmacological management of Kaposi’s sarcoma.” Expert opinion on pharmacotherapy 12.11 (2011): 1669-1690. http://hiv1tat-vaccines.info/pub…


Why do my American friends get sick by norovirus every Thanksgiving, but I’ve never seen a Russian citizen gotten sick by norovirus in her homeland?


, ,

Belonging to the RNA virus family Caliciviridae that can infect a wide variety of species, Norovirus is the bane of cruise ships, causing acute viral gastroenteritis (severe gastrointestinal upset characterized by vomiting and diarrhea), with ~20 million annual cases in the US (1) and accounting for ~18% acute gastroenteritis cases worldwide (2).

There are at least two different approaches to probing how noroviruses infect humans.

  • During a norovirus outbreak, why do only some get sick while others remain unaffected, even though they have similar likelihood of exposure?
  • How could a person remain unaffected from norovirus one time and yet get sick another time?

These two questions are really observations and they suggest two different types of processes may be involved in human norovirus infection, one that depends on genetic differences between humans, specifically on blood type antigen differences, and another that depends on gut microbiota, specifically on presence of gut commensal bacteria that express blood type antigens.

During a norovirus outbreak, why do only some get sick while others remain unaffected, even though they have similar likelihood of exposure?

  • Norovirus binds to specific cell-surface carbohydrates called histo-blood group antigens (HBGA) (3, 4).
  • Expressed not just on red blood cells but also on epithelial cells in the gastrointestinal, genitourinary and respiratory tracts, HBGAs can also be secreted into body fluids including saliva (5).
  • Expression of HBGAs varies widely among humans.
    • For e.g., ~20% of Europeans and North Americans have nonsense mutations in the FUT2 gene (codes for a fucosyltransferase enzyme) and as a result, don’t express HBGA on their epithelial cells (5). Such people are characterized as ‘nonsecretors‘ because they lack HBGA secretion in saliva.
    • OTOH, Asian nonsecretors have missense mutations in the same enzyme (6), which leads to small amounts of HBGAs in secretions.
    • Tests on healthy volunteers show that some nonsecretors are resistant to norovirus infection (7, 8).
    • However, even among the secretor phenotype, people with blood group B remained uninfected and asymptomatic in one study (7).
    • Epidemiological data corroborate the connection between FUT2 inactivation and strong but incomplete resistance to norovirus (9, 10, 11, 12). Incomplete implies other factors also contribute to resistance.
  • A combination of FUT2 and ABO blood group system seems to thus influence resistance or susceptibility to norovirus.
  • Different Norovirus strains recognize different HBGAs (4, 13), implying HBGA expression profile of individuals exposed to a particular norovirus would influence their likelihood of getting infected.
  • Thus norovirus strain and human HBGA (and blood group) expression pattern appear to represent a set of ‘keys’ and ‘locks’, respectively, implying that during a norovirus outbreak, people who get sick express cell-surface locks that can be opened by the keys expressed by a given norovirus strain whereas cells of other similarly exposed people who don’t get sick express locks norovirus keys can’t bind and thus they remain uninfected and therefore unaffected (14).
  • More recently, scientists found norovirus also bind other cell-surface carbohydrates, Ganglioside (15; see figure below from 16).

How could a person remain unaffected from norovirus one time and yet get sick another time?

Two possibilities could explain this phenomenon.

  • A person may be resistant to one but not another norovirus strain for reasons already outlined in the previous section, i.e., they express HBGA that one but not another norovirus strain can bind.
  • Presence of specific commensal bacteria in the gut could render a person susceptible to norovirus infection, specifically, presence of HBGA+ gut microbes (Yes, apparently even bacteria can express HBGA).

Norovirus was discovered in 1972 but until 2014 it couldn’t be cultured in human cells using classic cell culture techniques. This has stymied every aspect of its research from basic biology of how it infects cells and replicates to therapy as in drugs that could kill/inhibit it to control as in vaccines that could be effective against it.

  • The big surprise is though norovirus was thought to target Intestinal epithelium cells, the cells that form the gut barrier, a 2014 study (17) found that it instead targets B cell.
  • The other major surprise? The finding that gut microbial flora helped human norovirus effectively target and infect B cells. How? In this study, norovirus infected a human B cell line only in presence of HBGA+ bacteria (See figure below from 18).

How norovirus infects human cells isn’t yet completely understood. Clearly other as-yet unidentified receptors are involved. Meantime, this newly discovered role of HBGA+ gut microbiota in this process suggests a person may get infected one time but not another time, depending on presence or absence, respectively, of HGBA+ bacteria in their gut. Of course, such an idea is purely speculative at present and depends on whether or not HBGA+ bacteria are stable inhabitants of gut microflora.


1. Hall, Aron J., et al. “Norovirus disease in the United States.” Emerg Infect Dis 19.8 (2013): 1198-205. http://wwwnc.cdc.gov/eid/article…

2. Ahmed, Sharia M., et al. “Global prevalence of norovirus in cases of gastroenteritis: a systematic review and meta-analysis.” The Lancet infectious diseases 14.8 (2014): 725-730. https://www.researchgate.net/pro…

3. Huang, Pengwei, et al. “Noroviruses bind to human ABO, Lewis, and secretor histo-blood group antigens: identification of 4 distinct strain-specific patterns.” Journal of Infectious Diseases 188.1 (2003): 19-31. Identification of 4 Distinct Strain-Specific Patterns

4. Tan, Ming, and Xi Jiang. “Norovirus and its histo-blood group antigen receptors: an answer to a historical puzzle.” Trends in microbiology 13.6 (2005): 285-293.

5. Marionneau, Séverine, et al. “ABH and Lewis histo-blood group antigens, a model for the meaning of oligosaccharide diversity in the face of a changing world.” Biochimie 83.7 (2001): 565-573. https://www.researchgate.net/pro…

6. Kudo, Takashi, et al. “Molecular genetic analysis of the human Lewis histo-blood group system II. Secretor gene inactivation by a novel single missense mutation A385T in Japanese nonsecretor individuals.” Journal of Biological Chemistry 271.16 (1996): 9830-9837. Molecular Genetic Analysis of the Human Lewis Histo-blood Group System

7. Lindesmith, Lisa, et al. “Human susceptibility and resistance to Norwalk virus infection.” Nature medicine 9.5 (2003): 548-553. https://www.researchgate.net/pro…

8. Carlsson, Beatrice, et al. “The G428A nonsense mutation in FUT2 provides strong but not absolute protection against symptomatic GII. 4 Norovirus infection.” PloS one 4.5 (2009): e5593. http://journals.plos.org/plosone…

9. Tan, Ming, et al. “Outbreak studies of a GII‐3 and a GII‐4 norovirus revealed an association between HBGA phenotypes and viral infection.” Journal of medical virology 80.7 (2008): 1296-1301.

10. Van Trang, Nguyen, et al. “Association between norovirus and rotavirus infection and histo-blood group antigen types in Vietnamese children.” Journal of clinical microbiology 52.5 (2014): 1366-1374. Association between Norovirus and Rotavirus Infection and Histo-Blood Group Antigen Types in Vietnamese Children

11. Currier, Rebecca L., et al. “Innate susceptibility to norovirus infections influenced by FUT2 genotype in a United States pediatric population.” Clinical Infectious Diseases 60.11 (2015): 1631-1638. Innate Susceptibility to Norovirus Infections Influenced by FUT2 Genotype in a United States Pediatric Population

12. Hutson, Anne M., et al. “Norwalk virus infection associates with secretor status genotyped from sera.” Journal of medical virology 77.1 (2005): 116-120.

13. Tan, Ming, and Xi Jiang. “Norovirus–host interaction: multi-selections by human histo-blood group antigens.” Trends in microbiology 19.8 (2011): 382-388. http://www.ncbi.nlm.nih.gov/pmc/…

14. Carmona-Vicente, Noelia, et al. “Characterisation of a household norovirus outbreak occurred in Valencia (Spain).” BMC infectious diseases 16.1 (2016): 1. https://www.researchgate.net/pro…

15. Han, Ling, et al. “Gangliosides are ligands for human noroviruses.” Journal of the American Chemical Society 136.36 (2014): 12631-12637. http://pubs.acs.org/doi/pdfplus/…

16. Chemical and Engineering News, Stu Borman, Sep 8, 2014. New Ligand For Human Norovirus Could Inspire Treatments For Stomach Flu. New Ligand For Human Norovirus Could Inspire Treatments For Stomach Flu

17. Jones, Melissa K., et al. “Enteric bacteria promote human and mouse norovirus infection of B cells.” Science 346.6210 (2014): 755-759. https://www.researchgate.net/pro…

18. Karst, Stephanie M. “The influence of commensal bacteria on infection with enteric viruses.” Nature Reviews Microbiology 14.4 (2016): 197-204.