The far-reaching impacts of immunity and inflammation during the transition to lactation Barry Bradford June 2015

Large dairies

Early lactation – a unique challenge Overview Early lactation – a unique challenge Infection and metabolic disease links Long-lasting effects of early lactation problems Current research – novel solutions Transition disorders What is inflammation per se? When does it occur, esp. in cows? Is inflammation involved in metabolic Dos? Oxidative stress Overall model Antioxidants, metabolic modifiers, NSAIDs

The transition period ~ 40% metabolic ~ 60% infectious First lactation Third lactation ~ 40% metabolic ~ 60% infectious Ingvartsen, 2006

Transition cows have decreased immune function Lymphocyte function Neutrophil function Neutrophil function (iodination; ) and lymphocyte function (blastogenesis; ) are impaired during the weeks immediately before and after parturition. Goff and Horst,1997

Transition immune cells Enhanced inflammatory response Impaired chemotaxis Decreased phagocytosis Reduced killing ability All talk! Sordillo et al., 1995; Contreras et al., 2012; Kehrli et al., 1989; Nonnecke et al., 2003

Immunosuppression coincides with greater risk of infection Østergaard et al, 2005

Immune function predicts infection risk Infections 0% 16% 100%*** n = 7 Monocyte proliferation response to endotoxin n = 19 n = 5 Catalani et al, 2013

Infections increase ketosis risk Gröhn et al., 1989

Ketosis increases infection risk Duffield et al., 2009; Doohoo and Martin, 1984

Long-term consequences of transition problems Risk of leaving herd 3 X 1.5 X 3.5 X Seegers 2003; Deluyker 1991; Wittrock 2011; Ospina 2010; Seifi 2011

Suppressed immune function contributes to infectious disorders Infections promote metabolic disorders Metabolic problems increase infection risk Does inflammation provide a mechanistic link?

Inflammation Acute inflammation Associated with immune activation or tissue damage Swelling Pain Fever

Inflammation Chronic inflammation No outward signs Slightly elevated inflammatory mediators Alterations in signaling

Inflammation is associated with transition disorders Bertoni et al., 2008

Subacute, liver inflammation is common in postpartum cows Explain acute phase protein, especially haptoglobin Day relative to calving Sabedra, 2012 (thesis)

What causes transition inflammation?

Systemic inflammation

Systemic inflammation

Systemic inflammation

Systemic inflammation

Systemic inflammation

Systemic inflammation

Inflammation promotes ketosis Subclinical Ketosis 9% 27% P = 0.02, TNFα vs. control (18% decrease) Yuan et al., 2013

…and decreases milk yield P = 0.03, TNFα vs. control (15% decrease) C vs. T2 L vs. H3 0.03 0.76 Yuan et al., 2013

A vicious cycle Metabolic disorders promote Infections

Should we block inflammation?

Anti-inflammatories in early lactation (not currently approved) +9% P < 0.05 3 doses +7% P < 0.05 1 dose

Culling Rate C vs. M: P = 0.04

The Big Picture There is much crosstalk between metabolic and immune systems Inflammatory signals, driven by a wide variety of stimuli, are a key link Not always a negative The physiological milieu in the first week can have long-term impacts

A new possibility RNA interference: A mechanism whereby small RNA molecules can promote degradation of a specific transcript to knock down expression of a certain gene.

The discovery of RNAi Craig Mello and Andrew Fire, 2006 Nobel Prize

The central dogma

How does it work?

Protection and delivery

Silencing (knockdown)

The central dogma

The problem? Calving Poor appetite Ketosis Displaced abomasum Cull

How this could work Calving Increasing appetite Decreased NEFA Milk! Small Interfering RNA Increasing appetite Decreased NEFA Milk!

Why is this exciting One dose should be effective for at least a week

Off target effects can be avoided Why is this exciting Off target effects can be avoided Liver only Single gene target No genetic engineering involved RNA is a very safe “drug residue”

Hopefully….

CSIRO Australian Animal Health Laboratory

Thank you! Questions/comments: Barry Bradford Kansas State University bbradfor@ksu.edu @AnimNutr