Outlining a Project: Human Plague

I’ve had a bit of a blogging slump lately. I came back from the medieval congress with too many things on my mind to settle down to write a post. Nevertheless, it has been a productive couple of weeks. I’ve been working on an outline for one of the book projects that I mentioned quite a while back. I think its time to share some of those plans. I’m eager for feedback, criticism, suggestions… It won’t hurt my feelings at all and will be much appreciated! So here goes with the outline.

Working title: Human Plague: Natural History & Crisis Management

Introduction

Part I: A Natural History of Yersinia pestis

1. Origin, Evolution and Biogeography (also including bacteriology and reservoirs)

2. Anatomy of an Epidemic (transmission and epidemiology)

3. Natural History of an Infection (diagnosis, pathophysiology, immunology)

Part II: Crisis Management

4.Government Response (legal, economic, & political)

5. Medical Care

6. Mortuary Care

7. Children and the Plague

8. Crises of Faith and Response

9. Scapegoating the Other

10. Signs of Resilience

Part III: Modern Concerns

11. Weaponizing the Plague

12. Plague Today

Appendix: Chronology

The theory here is that the first part is a natural history from the point of view of biologists, public health, and medicine. ‘Human plague’ because a natural history of Yersinia pestis or ‘the plague’ would primarily be about rodents. These chapters will work in the entire history of human plague from evolution of the bacterium in central Asia to its movements for the next 1500 years. Certainly most of the epidemiology will include pre-modern epidemics.

The second maybe two-thirds of the planned book is influenced by my biosecurity training. It’s hard to think about the plague without thinking about the 1500 years of crisis management with the same organism. I expect that this section will change dramatically as I work on it. This outline is really just some of the elements of crisis management: government reaction, medical care, mortuary care, special populations (here represented by children), religious crises as the most evident social impact, and religious and racial persecution, and evidence of resilience.

The last section is pretty self-explanatory. It will review evidence of plague as a biological weapon and continuing concerns that it will be used as a weapon. It will end with an assessment of where we are today with plague as re-emerging disease.

My goal is to write this at about the same level of technical difficulty as this blog. I hope that it is useful to all of the many disciplines involved in plague research and response in the sciences and humanities.

It seems like I’m trying to put an awful lot in one book but I don’t really have a baseline to judge that by. Feedback would be much appreciated in the comments below or by email!

Leptin: Linking Malnutrition and Vulnerability to Infection

The correlation between malnutrition and vulnerability to infection has been well established (discussed previously here). While the immune dysfunction could be characterized it was not until the last 10-15 years that an exact mechanism began to resolve.

It all began with the discovery of a new hormone called leptin from an unexpected place, adipose tissue (fat cells). Leptin, a product of the obese (ob) gene, was discovered while looking for factors that regulate body fat. As a consequence of manipulating this gene in an attempt to regulate body fat, it was discovered that mice deficient in leptin had profound immune deficiencies.

The amount of leptin produced by adipose cells (fat cells) is directly proportional to the amount of fat in the cells. (The number of fat cells in adults does not change,  their size just shrinks or swells.) Leptin levels drop as body fat decreases or during fasting. Once leptin levels fall below a threshold, the lack of leptin puts the mammalian body into a starvation response. Areas of leptin activity are signaled by the production of the leptin receptor (OBR gene). Tissues producing the leptin receptor include areas of the hypothalamus that regulate body weight, bone mass, and appetite; ovarian cells, beta-cells of the pancreas, endothelial cells, and bone marrow stem cells, macrophages, and lymphocytes (1). Leptin influences cellular function by directly interacting with peripheral tissues including immune cells in lymph nodes, bone marrow, pancreatic function and bone homeostasis, but also by triggering hormonal changes in the brain, specifically in the hypothalamus. Study of leptin levels has opened previously unsuspected linked between central nervous system control and the development of the immune system.

The Hormonal Trigger of the Starvation Response

Leptin’s control of metabolism and the  immune system. (Ref. 2)

As long as leptin levels stay within normal levels, all of the functions displayed above function normally. As the leptin levels drop, many of these functions are adversely effected. It is a wide-spread trigger for a starvation response.  Why cripple the immune response during starvation? My best guess would be because of the huge energy expenditure required to keep the immune response running normally, especially in cellular proliferation.

When leptin levels drop too low, physiological dysfunction occurs in haematopoiesis (blood cell production), bone metabolism, glucose metabolism and angiogenesis (blood vessel production and maintenance) and immune suppression involving both the innate (non-specific) and adaptive immune system. During malnutrition, the size of the thymus gland shrinks with diminished T cell development. This may be one of the long-term consequences of childhood malnutrition. Children with congenitally low leptin levels have a higher mortality rate due to childhood infections (2).

Leptin modulates immune function (ref. 1)

With all the functions illustrated above, it’s not very surprising that malnutrition is the second most common cause of secondary immune suppression today (2). Alternatively, high leptin levels in obese people have also been linked with increased vulnerability to infection possibly through the development of leptin resistance due to prolonged exposure to excessively high levels of leptin (2). Food for thought considering that obesity was one of the only risk factors for a poor outcome during the recent H1N1 influenza pandemic. We have come to expect malnutrition induced immune suppression, but we may also have to consider over-nutrition induced immune suppression and/or autoimmunity as outcomes of immune dysregulation due to leptin resistance.

References:

[1] La Cava, A., & Matarese, G. (2004). The weight of leptin in immunity Nature Reviews Immunology, 4 (5), 371-379 DOI: 10.1038/nri1350

[2] Procaccini C, Jirillo E, & Matarese G (2012). Leptin as an immunomodulator. Molecular aspects of medicine, 33 (1), 35-45 PMID: 22040697

Tracking a Live Yersinia pestis Infection with Bioluminescence

The day has finally arrived when an experimental infection can be tracked real-time over the entire course of the infection. Developing a natural history of a rapidly lethal infectious disease has been a challenge because individual variation clouds the progression and individuals can only be studied after death.

The traditional method to study these infections involves infecting many animals so that cohorts of animals can be sacrificed at set time points, have their organs harvested and bacterial load of the organ determined. Some of the flaws of this method are that the right organs may not be selected to survey and individual variation in infection progression means that wide variation may be found at the time points.

Tracking the progression of an infection with bioluminescence allows the infection to run its full course within each experimental animal, rather than taking cohorts at time points. Elizabeth Carniel’s lab at the Institut Pasteur in Paris created bioluminescent Yersinia pestis, and after doing all the controls to ensure a consistent signal under all growth conditions, demonstrated that a live bubonic plague case can be tracked real-time until  death .

In the first figure below the mouse was sacrificed before septicemia set in to correlate the external signals with specific organs. The bioluminescent Y. pestis was injected at the midline near the navel into the linea alba, a tendon-like covering of the abdominal muscles, to simulate a flea bite. Signals represent the injection site, lymph nodes, and the spleen and liver.

Identifying the bioluminescent signals by dissection. 1. axillary lymph nodes, 2. liver, 3. injection site, 4. inguinal lymph node, and 5. spleen. (Nham et al, 2012)

For 74% of the animals injected, the infection followed the same spread pattern. In all the animals the injection site was lit up from the first day. From there it spread to the inguinal lymph node and then surprisingly to the axillary lymph node. The signal then concentrated in the spleen and liver before it becomes completely systemic. Nham et al (2012) note that the signal completely covers the animal from the their ears to the tails. Confirmation of septicemia came from Y. pestis isolated from blood after the death of the animal. Death occurred on average by the sixth day, coming very quickly after septicemia.

Progression of a bubonic plague infection (Nham et al, 2012)

Some of the mice provided clues on how the bioluminescence jumped from the inguinal node to a axillary node. As the linear glow below suggests, they found a lymph vessel that connects the inguinal node to the axillary node. It is consistent with Y. pestis spreading to linked lymph nodes. Confirmation of the lymph vessel linking the inguinal and axillary nodes is shown by bioluminescence and by dye injected dissected mouse in the figure below.

Identification of the lymph vessel connecting inguinal and axillary lymph nodes. (Nham et al, 2012)

The signal next appears under the diaphragm in areas consistent with the liver and spleen (shown in the first figure). This would not necessarily be a direct line from the axillary lymph node to the spleen and liver but that the spleen and liver became infected at about the same time as the axillary node. Colonization of the liver and spleen are related to their blood clearing functions and are indications of a very early phase of septicemia too low to yield systemic bioluminescence.  Death occurred on average by the sixth day, coming very quickly after septicemia.  Nham et al (2012: 5) report that their “results revealed two important phenomena: (i) the variations in the kinetics of bacterial spread were essentially attributable to the length of time the signal remained limited to the injection site, and (ii) as soon as the signal reached lymph nodes, the disease progressed very rapidly, leading to the animal death within two days.” Time between the injection site and first lymph node varied from one to seven days.

The 26% of mice that did not follow this pattern died rapidly with symptoms of a direct septicemic infection (skipping lymph node signals entirely). This suggests that they either hit a blood vessel at the injection site or may have penetrated the abdominal cavity with the injection.

This study is an important first step in developing the method. From here there are many studies than could be done including the effect of changing individual genes on virulence and progression.

Reference:

Nham, T., Filali, S., Danne, C., Derbise, A., & Carniel, E. (2012). Imaging of Bubonic Plague Dynamics by In Vivo Tracking of Bioluminescent Yersinia pestis PLoS ONE, 7 (4) DOI: 10.1371/journal.pone.0034714