Getting to the Brain by Hijacking miRNA: The EEE story

The mechanism by which Eastern Equine Encephalitis (EEE), a deadly mosquito-borne viral disease with a 50% mortality rate, causes its characteristic illness is the subject of a pathbreaking article in Nature by authors from Pitt's Center for Vaccine Research. 

The paper is focused on the role of miRNAs and their interaction with viral RNA. miRNAs are small pieces of RNA that cells use to regulate the expression of genes. miRNAs have not been thought to have a role in controlling viral genes. In the case of EEE, however, William Klimstra and colleagues found an miRNA that binds to the virus, blunting its ability to infect specific cells of the immune system and, consequently, stops the triggering of an immune response.

This suppression of host immune defenses by exploiting--or hijacking, as the authors put it--host miRNAs allows the virus to reek havoc in the central nervous system causing the signs and symptoms of encephalitis.

Furthermore, the viral sequences that bind the miRNA serve a dual purpose, enhancing replication in the mosquito vector.

The elegance and ingenuity of this viral mechanism is truly fascinating and it will be important to determine if other viruses use similar mechanisms.

Hantavirus: Our Very Own Special Pathogen

That most exotic diseases occur outside the US relegates infectious disease physicians to treating scores of patients with MRSA; diabetic foot infections; pneumonia; urinary tract infections; and the occasional zebra.

One domestic disease that packs all of the punch of its more well known foreign brothers-in-arms, however, is the rodent-associated hantavirus.

Hantavirus Pulmonary Syndrome (HPS) first came to wide notice after a headline-grabbing outbreak occurred in the Navajo-inhabited Four Corners region of the western US in 1993 (see the book Of Mice, Men, and Microbes for a great overview). Since that time, sporadic cases have occurred including an outbreak last year at Yosemite National Park.

A recent paper authored by CDC officials details 20 years of hantavirus infections in the US. Some important points include that a total of 624 cases occurred since 1993 and 96% of cases occurred west of the Mississippi River.

The aspect of hantavirus that I find most fascinating is the association of outbreaks with high amounts of rainfall. When high levels of rainfall occur, such as during an El Niño, rodent populations surge because of the abundance of food available. Such rodent population surges make contact with humans much more common and, consequently, human cases of hantavirus occur. In fact, this correlation was known in Navajo medical traditions long before recent outbreaks.

Though rare, it is important to consider HPS in patients with unexplained pulmonary edema and fever, especially if hemoconcentration is present and the patient is relatively young.

Raw Milk: A Return to the Primitive?

It’s unfortunate that in the 21st Century the American Academy of Pediatrics has to release a policy statement regarding the danger of consuming raw milk. Over 100 years ago, Louis Pasteur discovered that heating wine could prevent it from souring by killing the bacteria responsible. The process was named pasteurization in honor of Pasteur (but the use of heat to preserve food stuffs had been practiced before). It seems that the ongoing fad of raw milk consumption represents a return to the primitive.

During my critical care fellowship, I took care of a patient who consumed raw milk who developed Campylobacter gastroenteritis and subsequent paralysis secondary to Guillan-Barre Syndrome. Though the patient knowingly consumed the raw milk, he subsequently filed a lawsuit labeling the product he consumed “defective”.

To me, the consumption of raw milk represents a dangerous return to a pre-industrial practice that needlessly increases risk. Though I believe it is each adult’s right to consume this—by definition and design—defective product, I find it highly questionable. 

Breast Milk vs. Hepatitis C: Breast Milk Wins

An interesting paper published in the Journal of Infectious Diseases details the discovery that human breast milk has antiviral activity against the hepatitis C virus (HCV). 

Approximately 5-10% of deliveries by HCV positive women result in perinatal transmission of HCV to the child. Transmission is related to HCV viremia, HIV co-infection, prolonged membrane rupture, and intrapartum exposure to maternal blood. Breast milk, though it contains the virus, is not thought to be a major risk.

This paper adds further weight to the safety of HCV positive mothers breastfeeding their children. In this study, researchers incubated HCV--at concentrations 1000x higher than that found in breast milk--with breast milk from HCV uninfected women. Infectivity after incubation with breast milk was reduced 2-3 fold for all genotypes of the virus. Further experimentation confirmed that the mechanism underlying the antiviral effect was due to free fatty acids that disrupt the viral envelope (see graphic).

In an accompanying editorial, Ravi Jhaveri of UNC writes: "After reading this article, when we clinicians next encounter an HCV-infected patient that just delivered a healthy infant and wants to breastfeed, we have yet another reason to say 'Breast is Best'."

Elite HIV Controllers: The Exceptions that Prove a Cure is Possible?

Today I saw a patient who was infected with HIV in the 1970s and is alive today. In the modern era of HIV treatment in the US, seeing people survive long term with HIV is commonplace. In fact, it is projected that in a few years individuals over 50 will comprise half the cases in the US (as I was quoted saying in this article).

The interesting thing about this patient, however, is that the patient remains alive without the benefit of drugs. HIV has been held at bay by the patient's immune system. The patient is what we refer to as a long-term non-progressor. These individuals exhibit no overt signs of immune destruction by HIV despite years of infection.

The terminology defining long-term non-progressors can get confusing as they are divided into one of two types:

1. Elite controllers: no measurable virus detected using routine test
2. Viremic controllers: viral loads < 2000 copies/mL

The patient I saw today is an elite controller, with no measurable virus in the blood. 

Studying the mysteries of how elite controllers control HIV replication is thought to be key to developing a cure (see great graphic from amFAR) for HIV. Most current hypothesis are currently focused on what immune responses are operative in these patients (it is not thought that the HIV virus is defective in these patients nor the CD4 cells immune from infection).